This invention relates generally to modulators of chemokine receptor activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory diseases such as asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis.
Chemokines are chemotactic cytokines, of molecular weight 6-15 kDa, that are released by a wide variety of cells to attract and activate, among other cell types, macrophages, T and B lymphocytes, eosinophils, basophils and neutrophils (reviewed in Luster, New Eng. J Med., 338, 436-445 (1998) and Rollins, Blood, 90, 909-928 (1997)). There are two major classes of chemokines, CXC and CC, depending on whether the first two cysteines in the amino acid sequence are separated by a single amino acid (CXC) or are adjacent (CC). The CXC chemokines, such as interleukin-8 (IL-8), neutrophil-activating protein-2 (NAP-2) and melanoma growth stimulatory activity protein (MGSA) are chemotactic primarily for neutrophils and T lymphocytes, whereas the CC chemokines, such as RANTES, MIP-1xcex1, MIP-1xcex2, the monocyte chemotactic proteins (MCP-1, MCP-2, MCP-3, MCP-4, and MCP-5) and the eotaxins (-1, -2, and -3) are chemotactic for, among other cell types, macrophages, T lymphocytes, eosinophils, dendritic cells, and basophils. There also exist the chemokines lymphotactin-1, lymphotactin-2 (both C chemokines), and fractalkine (a CXXXC chemokine) that do not fall into either of the major chemokine subfamilies.
The chemokines bind to specific cell-surface receptors belonging to the family of G-protein-coupled seven-transmembrane-domain proteins (reviewed in Horuk, Trends Pharm. Sci., 15, 159-165 (1994)) which are termed xe2x80x9cchemokine receptors.xe2x80x9d On binding their cognate ligands, chemokine receptors transduce an intracellular signal through the associated trimeric G proteins, resulting in, among other responses, a rapid increase in intracellular calcium concentration, changes in cell shape, increased expression of cellular adhesion molecules, degranulation, and promotion of cell migration. There are at least ten human chemokine receptors that bind or respond to CC chemokines with the following characteristic patterns: CCR-1 (or xe2x80x9cCKR-1xe2x80x9d or xe2x80x9cCC-CKR-1xe2x80x9d) [MIP-1xcex1, MCP-3, MCP-4, RANTES] (Ben-Barruch, et al., Cell, 72, 415-425 (1993), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-2A and CCR-2B (or xe2x80x9cCKR-2Axe2x80x9d/xe2x80x9cCKR-2Bxe2x80x9d or xe2x80x9cCC-CKR-2Axe2x80x9d/xe2x80x9cCC-CKR-2Bxe2x80x9d) [MCP-1, MCP-2, MCP-3, MCP-4, MCP-5] (Charo et al., Proc. Natl. Acad. Sci. USA, 91, 2752-2756 (1994), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-3 (or xe2x80x9cCKR-3xe2x80x9d or xe2x80x9cCC-CKR-3xe2x80x9d) [eotaxin-1, eotaxin-2, RANTES, MCP-3, MCP-4] (Combadiere, et al., J. Biol. Chem., 270, 16491-16494 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-4 (or xe2x80x9cCKR-4xe2x80x9d or xe2x80x9cCC-CKR-4xe2x80x9d) [TARC, MIP-1xcex1, RANTES, MCP-1] (Power et al., J. Biol. Chem., 270, 19495-19500 (1995), Luster, New Eng. J. Med., 338, 436-445 (1998)); CCR-5 (or xe2x80x9cCKR-5xe2x80x9d OR xe2x80x9cCC-CKR-5xe2x80x9d) [MIP-1xcex1, RANTES, MIP-1xcex2] (Sanson, et al., Biochemistry, 35, 3362-3367 (1996)); CCR-6 (or xe2x80x9cCKR-6xe2x80x9d or xe2x80x9cCC-CKR-6xe2x80x9d) [LARC] (Baba et al., J. Biol. Chem., 272, 14893-14898 (1997)); CCR-7 (or xe2x80x9cCKR-7xe2x80x9d or xe2x80x9cCC-CKR-7xe2x80x9d) [ELC] (Yoshie et al., J. Leukoc. Biol. 62, 634-644 (1997)); CCR-8 (or xe2x80x9cCKR-8xe2x80x9d or xe2x80x9cCC-CKR-8xe2x80x9d) [I-309, TARC, MIP-1xcex2] (Napolitano et al., J. Immunol., 157, 2759-2763 (1996), Bernardini et al., Eur. J. Immunol., 28, 582-588 (1998)); and CCR-10 (or xe2x80x9cCKR-10xe2x80x9d or xe2x80x9cCC-CKR-10xe2x80x9d) [MCP-1, MCP-3] (Bonini et al, DNA and Cell Biol., 16, 1249-1256 (1997)).
In addition to the mammalian chemokine receptors, mammalian cytomegaloviruses, herpesviruses and poxviruses have been shown to express, in infected cells, proteins with the binding properties of chemokine receptors (reviewed by Wells and Schwartz, Curr. Opin. Biotech., 8, 741-748 (1997)). Human CC chemokines, such as RANTES and MCP-3, can cause rapid mobilization of calcium via these virally encoded receptors. Receptor expression may be permissive for infection by allowing for the subversion of normal immune system surveillance and response to infection. Additionally, human chemokine receptors, such as CXCR4, CCR2, CCR3, CCR5 and CCR8, can act as co-receptors for the infection of mammalian cells by microbes as with, for example, the human immunodeficiency viruses (HIV).
Chemokine receptors have been implicated as being important mediators of inflammatory, infectious, and immunoregulatory disorders and diseases, including asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. For example, the chemokine receptor CCR-3 plays a pivotal role in attracting eosinophils to sites of allergic inflammation and in subsequently activating these cells. The chemokine ligands for CCR-3 induce a rapid increase in intracellular calcium concentration, increased expression of cellular adhesion molecules, cellular degranulation, and the promotion of eosinophil migration. Accordingly, agents which modulate chemokine receptors would be useful in such disorders and diseases. In addition, agents which modulate chemokine receptors would also be useful in infectious diseases such as by blocking infection of CCR3 expressing cells by HIV or in preventing the manipulation of immune cellular responses by viruses such as cytomegaloviruses.
A substantial body of art has accumulated over the past several decades with respect to substituted piperidines and pyrrolidines. These compounds have implicated in the treatment of a variety of disorders.
WO 98/25604 describes spiro-substituted azacycles which are useful as modulators of chemokine receptors: 
wherein R1 is C1-6 alkyl, optionally substituted with functional groups such as xe2x80x94NR6CONHR7, wherein R6 and R7 may be phenyl further substituted with hydroxy, alkyl, cyano, halo and haloalkyl. Such spiro compounds are not considered part of the present invention.
WO 95/13069 is directed to certain piperidine, pyrrolidine, and hexahydro-1H-azepine compounds of general formula: 
wherein A may be substituted alkyl or Z-substituted alkyl, with Zxe2x95x90NR6a or O. Compounds of this type are claimed to promote the release of growth hormone in humans and animals.
WO 93/06108 discloses pyrrolobenzoxazine derivatives as 5-hydroxytryptamine (5-HT) agonists and antagonists: 
wherein A is lower alkylene and R4 may be phenyl optionally substituted with halogen.
U.S. Pat. No. 5,668,151 discloses Neuropeptide Y (NPY) antagonists comprising 1,4-dihydropyridines with a piperidinyl or tetrahydropyridinyl-containing moiety attached to the 3-position of the 4-phenyl ring: 
wherein B may be NH, NR1, O, or a bond, and R7 may be substituted phenyl, benzyl, phenethyl and the like.
Patent publication EP 0 903 349 A2 discloses CCR-3 receptor antagonists comprising cyclic amines of the following structure: 
wherein T and U may be both nitrogen or one of T and U is nitrogen and the other is carbon and E may be xe2x80x94NR6CONR5xe2x80x94 and others.
These reference compounds are readily distinguished structurally by either the nature of the urea functionality, the attachment chain, or the possible substitution of the present invention. The prior art does not disclose nor suggest the unique combination of structural fragments which embody these novel piperidine amides as having activity toward the chemokine receptors.
Accordingly, one object of the present invention is to provide novel agonists or antagonists of CCR-3, or pharmaceutically acceptable salts or prodrugs thereof.
It is another object of the present invention to provide pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide a method for treating inflammatory diseases and allergic disorders comprising administering to a host in need of such treatment a therapeutically effective amount of at least one of the compounds of the present invention or a pharmaceutically acceptable salt or prodrug form thereof.
It is another object of the present invention to provide novel N-ureidoheterocycloalkyl-piperidines for use in therapy.
It is another object of the present invention to provide the use of novel N-ureidoheterocycloalkyl-piperidines for the manufacture of a medicament for the treatment of allergic disorders.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein E, Z, M, J, K, L, Q, R1, R2, R3, and R4 are defined below, are effective modulators of chemokine activity.
[1] Thus, in a first embodiment, the present invention provides novel compounds of formula (I): 
or stereoisomers or pharmaceutically acceptable salts thereof, wherein:
M is absent or selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
Q is selected from CH2, CHR5, CHR13, CR13R13, and CR5R13;
J and K are independently selected from CH2, CHR5, CHR6, CR6R6 and CR5R6;
L is selected from CHR5 and CR5R6;
with the proviso:
when M is absent, J is selected from CH2, CHR5, CHR13, and CR5R13;
Z is selected from O, S, NR1a, C(CN)2, CH(NO2), and CHCN;
R1a is selected from H, C1-6 alkyl, C3-6 cycloalkyl, CONR1bR1b, OR1b, CN, NO2, and (CH2)wphenyl;
R1b is independently selected from H, C1-3 alkyl, C3-6 cycloalkyl, and phenyl; 
G is selected from a bond, Cxe2x95x90O, and SO2;
Ring B is a 5, 6, or 7 membered saturated heterocyclic ring wherein the heterocycle ring includes xe2x80x94NR9xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94NR9dC(O)xe2x80x94, xe2x80x94C(O)NR9dxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR9dC(O)NR9d, xe2x80x94NR9dC(O)Oxe2x80x94, xe2x80x94NR9dS(O)2xe2x80x94, xe2x80x94S(O)2NR9d, or xe2x80x94OC(O)NR9dxe2x80x94, the heterocycle ring being optionally substituted by 0-2 R8;
R1 and R2 are independently selected from H, C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, and (CH2)rC3-6 cycloalkyl;
R3 is selected from methyl substituted with 0-1 R10, C2-8 alkyl substituted with 0-3 R7, C3-8 alkenyl substituted with 0-3 R7, C3-8 alkynyl substituted with 0-3 R7, C2 fluoroalkyl, C3-8 haloalkyl, a (CR3xe2x80x2R3xe2x80x3)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15 and a (CR3xe2x80x2R3xe2x80x3)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15;
R3xe2x80x2 and R3xe2x80x3 , at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CH2)qC(O)R4b, (CH2)qC(O)NR4aR4axe2x80x2, (CH2)qC(O)OR4b, and a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R4c;
R4a and R4axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R4b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, (CH2)rC3-6 cycloalkyl, C3-8 alkynyl, and phenyl;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
R5 is selected from a (CR5xe2x80x2R5xe2x80x3)txe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16 and a (CR5xe2x80x2R5xe2x80x3)t-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16;
R5xe2x80x2 and R5xe2x80x3, at each occurrence, are selected from H, C1-6 alkyl, (CH2)rC3-6 cycloalkyl, and phenyl;
R6, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rNR6aR6axe2x80x2, (CH2)rOH, (CH2)rOR6b, (CH2)rSH, (CH2)rSR6b, (CH2)rC(O)OH, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, (CH2)rC(O)OR6b, (CH2)rOC(O)R6b, (CH2)rS(O)pR6b, (CH2)rS(O)2NR6aR6axe2x80x2, (CH2)rNR6dS(O)2R6b, and (CH2)tphenyl substituted with 0-3 R6c;
R6aand R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
with the proviso that when any of J or K is CR6R6 and R6 is cyano, or bonded to the carbon to which it is attached through a heteroatom, the other R6 is not cyano, or bonded to the carbon to which it is attached through a heteroatom;
R7 is selected from NO2, CN, NR7aR7axe2x80x2, OH, OR7d, C(O)H, C(O)OH, C(O)R7b, C(O)NR7aR7axe2x80x2, NR7fC(O)OR7d, OC(O)NR7aR7axe2x80x2, NR7fC(O)R7b, NR7fC(O)NR7fR7f, C(O)OR7d, OC(O)R7b, C(xe2x95x90NR7f)NR7aR7axe2x80x2, NHC(xe2x95x90NR7f)NR7fR7f, S(O)pR7b, S(O)2NR7aR7axe2x80x2, NR7fS(O)2R7b, C1-6 haloalkyl;
R7aand R7axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R7e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
alternatively, R7aand R7axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR7h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R7b, at each occurrence, is selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R7e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R7e;
R7d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R7e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R7e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R7e;
R7e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR7fR7f, (CH2)rphenyl, and a heterocycle substituted with 0-1 R7g, wherein the heterocycle is selected from imidazole, thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole,;
R7f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R7g is selected from methyl, ethyl, acetyl, and CF3;
R7h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R7f, C(O)OR7i, and SO2R7i;
R7i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
R8 is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C1-6haloalkyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R8c, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R8c;
R8a, at each occurrence, are selected from H, C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R8e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R8e;
R8b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-2 R8e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R8e;
R8c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, (CF2)rCF3, NO2, CN, (CH2)rNR8fR8f, (CH2)rOH, (CH2)rOC1-4 alkyl, (CH2)rSC1-4 alkyl, (CH2)rC(O)OH, (CH2)rC(O)R8a, (CH2)rC(O)NR8fR8f, (CH2)rNR8fC(O)R8a, (CH2)rC(O)OC1-4 alkyl, (CH2)rOC(O)R8b, (CH2)rS(O)pR8b, (CH2)rS(O)2NR8fR8f, (CH2)rNR8fS(O)2R8b, and (CH2)rphenyl substituted with 0-3 R8e;
R8e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSH, (CH2)rSC1-5 alkyl, (CH2)rNR8fR8f, and (CH2)rphenyl;
R8f, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R9 is selected from H, CH3, C2-6 alkyl substituted with 0-3 R9a, C3-8 alkenyl, C3-8 alkynyl, C1-6haloalkyl, (CHRxe2x80x2)rC(O)C1-6 alkyl substituted with 0-3 R9j, (CHRxe2x80x2)rC(O)OC1-6 alkyl substituted with 0-3 R9b, (CHRxe2x80x2)rC(O)NR9dR9dxe2x80x2, (CHRxe2x80x2)rS(O)2C1-6 alkyl, S(O)2C1-6 haloalkyl, (CHRxe2x80x2)rS(O)2NR9dR9d, R9xe2x80x2, (CHRxe2x80x2)rC(O)R9xe2x80x2, (CHRxe2x80x2)rC(O)NR9dR9xe2x80x2, (CHRxe2x80x2)rS(O)2R9xe2x80x2, and (CHRxe2x80x2)rS(O)2NR9dR9xe2x80x2;
R9xe2x80x2, at each occurrence, is independently selected from (CHRxe2x80x2)rC3-6 cycloalkyl substituted with 0-3 R9e, (CHRxe2x80x2)rphenyl substituted with 0-3 R9c, (CHRxe2x80x2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c,
R9a, at each occurrence, is selected from CN, NO2, OC1-5 alkyl, CF3, OH, OC1-5 alkyl, OC(O)C1-5 alkyl, SC1-5 alkyl, S(O)pC1-5 alkyl, and NR9dR9dxe2x80x2;
R9b, at each occurrence, is selected from C3-6 cycloalkyl, CN, (CF2)rCF3, (CH2)qOC1-5 alkyl, (CH2)qOH, (CH2)qSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)qNR9dR9dxe2x80x2;
R9c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CHRxe2x80x2)rC(O)C1-5 alkyl, (CHRxe2x80x2)rC(O)OC1-5 alkyl, (CHRxe2x80x2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2;
provided that if R9c is attached to a carbon attached to the nitrogen on Ring B, then R9c is selected from (CH2)qOH, (CH2)qOC1-5 alkyl, (CH2)qSC1-5 alkyl, (CH2)qS(O)qC1-5 alkyl, and (CH2)qNR9dR9dxe2x80x2;
R9d and R9dxe2x80x2, at each occurrence, are independently selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
alternatively, R9dand R9dxe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR9h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R9e, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CHRxe2x80x2)rC(O)OC1-5 alkyl, (CHRxe2x80x2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2, or alternatively, two R9e on the same carbon atom form xe2x95x90O;
R9h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R9f, C(O)OR9i, and SO2R9i;
R9i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
R9j, at each occurrence, is selected from C3-6 cycloalkyl, CN, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2;
R10 is selected from C(O)H, C(O)OH, C(O)R10b, C(O)NR10aR10axe2x80x2, C(O)OR10d, C(xe2x95x90NR10f)NR10aR10axe2x80x2, S(O)R10b, S(O)2R10b, S(O)2NR10aR10axe2x80x2;
R10a and R10axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R10e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R10e;
alternatively, R10a and R10axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR10h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R10b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R10e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R10e;
R10d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R10e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R10e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R10e;
R10e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR10fR10f, (CH2)rphenyl, and a heterocycle substituted with 0-1 R10g, wherein the heterocycle is selected from imidazole, thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole,;
R10f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R10g is selected from methyl, ethyl, acetyl, and CF3;
R10h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R10f, C(O)OR10i, and SO2R10i;
R10i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
R13, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, (CF2)wCF3, (CH2)qNR13aR13axe2x80x2, (CH2)qOH, (CH2)qOR13b, (CH2)qSH, (CH2)qSR13b, (CH2)wC(O)OH, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)qNR13dC(O)R13a, (CH2)wC(O)OR13b, (CH2)qOC(O)R13b, (CH2)wS(O)pR13b, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)qNR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R15, at each occurrence, is selected from xe2x95x90O, C1-8 alkyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR15aR15axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O) (CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(O)NR15aR15a, (CHRxe2x80x2)rNR15fC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rNR15fC(O)NR15fR15f, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR15d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rC(xe2x95x90NR15f)NR15aR15axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR15f)NR15fR15f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR15b, (CHRxe2x80x2)rS(O)2NR15aR15axe2x80x2, (CHRxe2x80x2)rNR15fS(O)2(CHRxe2x80x2)rR15b, C1-6haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, (CHRxe2x80x2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
Rxe2x80x2, at each occurrence, is independently selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, (CH2)rC3-6 cycloalkyl, and (CH2)rphenyl substituted with R15e;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R15e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
alternatively, R15aand R15axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR15h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R15b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-6 carbocyclic residue substituted with 0-3 R15e, and (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e;
R15d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, methyl, CF3, C2-6 alkyl substituted with 0-3 R15e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R15e, and a (CH2)r5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R15e;
R15e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, C(O)C1-6 alkyl, C(O)OC1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR15fR15f, (CH2)rphenyl, and a heterocycle substituted with 0-1 R15g, wherein the heterocycle is selected from imidazole, thiazole, oxazole, pyrazole, 1,2,4-triazole, 1,2,3-triazole, isoxazole, and tetrazole,;
R15f, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl;
R15g is selected from methyl, ethyl, acetyl, and CF3;
R15h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R15f, C(O)OR15i, and SO2R15i;
R15i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
R16, at each occurrence, is selected from C1-8 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, Br, I, F, NO2, CN, (CHRxe2x80x2)rNR16aR16axe2x80x2, (CHRxe2x80x2)rOH, (CHRxe2x80x2)rO(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rSH, (CHRxe2x80x2)rC(O)H, (CHRxe2x80x2)rC(O)OH, (CHRxe2x80x2)rC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(O)O(CHRxe2x80x2)rR16d, (CHRxe2x80x2)rOC(O)(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rC(xe2x95x90NR16f)NR16aR16axe2x80x2, (CHRxe2x80x2)rNHC(xe2x95x90NR16f)NR16fR16f, (CHRxe2x80x2)rS(O)p(CHRxe2x80x2)rR16b, (CHRxe2x80x2)rS(O)2NR16aR16axe2x80x2, (CHRxe2x80x2)rNR16fS(O)2(CHRxe2x80x2)rR16b, C1-6haloalkyl, C2-8 alkenyl substituted with 0-3 Rxe2x80x2, C2-8 alkynyl substituted with 0-3 Rxe2x80x2, and (CHRxe2x80x2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-5 R16e, and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
alternatively, R16a and R16axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR16h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R16b, at each occurrence, is selected from C1-6 alkyl, C3-8 alkenyl, C3-8 alkynyl, a (CH2)rC3-6 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R16e;
R16d, at each occurrence, is selected from C3-8 alkenyl, C3-8 alkynyl, C1-6 alkyl substituted with 0-3 R16e, a (CH2)rxe2x80x94C3-10 carbocyclic residue substituted with 0-3 R16e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R16e;
R16e, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, OH, SH, (CH2)rSC1-5 alkyl, (CH2)rNR16fR16f, and (CH2)rphenyl;
R16f, at each occurrence, is selected from H, C1-5 alkyl, and C3-6 cycloalkyl, and phenyl;
R16h is selected from H, C1-6 alkyl, C3-6 cycloalkyl, (CH2)rphenyl, C(O)R16f, C(O)OR16i, and SO2R16i;
R16i, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl;
m, at each occurrence, is independently selected from 0, 1, and 2;
t, at each occurrence, is independently selected from 1 and 2;
w, at each occurrence, is independently selected from 0 and 1;
r, at each occurrence, is independently selected from 0, 1, 2, 3, 4, and 5;
q, at each occurrence, is independently selected from 1, 2, 3, 4, and 5; and
p, at each occurrence, is independently selected from 0, 1, and 2.
[2] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R4 is absent, taken with the nitrogen to which it is attached to form an N-oxide, or selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, and (CH2)r-phenyl substituted with 0-3 R4c;
R4c, at each occurrence, is selected from C1-6 alkyl, C2-8 alkenyl, C2-8 alkynyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rNR4aR4axe2x80x2, and (CH2)rphenyl;
R1 and R2 are independently selected from H and C1-4 alkyl;
R6, at each occurrence, is selected from C1-4 alkyl, C2-8 alkenyl, C2-8 alkynyl, (CH2)rC3-6 cycloalkyl, (CF2)rCF3, CN, (CH2)rOH, (CH2)rOR6b, (CH2)rC(O)R6b, (CH2)rC(O)NR6aR6axe2x80x2, (CH2)rNR6dC(O)R6a, and (CH2)tphenyl substituted with 0-3 R6c;
R6a and R6axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R6c;
R6c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, (CH2)rSC1-5 alkyl, and (CH2)rNR6dR6d;
R6d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
R13, at each occurrence, is selected from C1-4 alkyl, C3-6 cycloalkyl, (CH2)NR13aR13axe2x80x2, (CH2)OH, (CH2)OR13b, (CH2)wC(O)R13b, (CH2)wC(O)NR13aR13axe2x80x2, (CH2)NR13dC(O)R13a, (CH2)wS(O)2NR13aR13axe2x80x2, (CH2)NR13dS(O)2R13b, and (CH2)w-phenyl substituted with 0-3 R13c;
R13a and R13axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13b, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, and phenyl substituted with 0-3 R13c;
R13c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rOH, and (CH2)rNR13dR13d;
R13d, at each occurrence, is selected from H, C1-6 alkyl, and C3-6 cycloalkyl;
q is selected from 1, 2, and 3; and
r is selected from 0, 1, 2, and 3.
[3] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
R3 is selected from a methyl substituted with 0-1 R10, C2-8 alkyl substituted with 0-3 R7, a (CR3xe2x80x2H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indazolyl, isoxazolinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R16; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
[4] In another embodiment, the present invention provides novel compounds of formula (I), wherein:
Ring B is a 5 or 6 membered heterocycle ring wherein the heterocycle ring includes xe2x80x94NR9xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)pxe2x80x94, xe2x80x94NR9dC(O)xe2x80x94, xe2x80x94C(O)NR9dxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94OC(O)xe2x80x94, xe2x80x94NR9dC(O)NR9d, xe2x80x94NR9dC(O)Oxe2x80x94, xe2x80x94OC(O)NR9dxe2x80x94, xe2x80x94NR9dS(O)2xe2x80x94, or xe2x80x94S(O)2NR9d, the heterocycle ring being optionally substituted by 0-2 R8;
R9 is selected from H, CH3, C2-6 alkyl substituted with 0-3 R9a, C3-8 alkenyl, C3-8 alkynyl, C1-3 haloalkyl, (CH2)rC(O)C1-6 alkyl substituted with 0-2 R9j, (CH2)rC(O)OC1-6 alkyl substituted with 0-3 R9b, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rS(O)2C1-6 alkyl, S(O)2C1-6 trifluoromethyl, (CH2)rC(O)R9xe2x80x2, (CH2)rC(O)NR9dR9xe2x80x2, (CH2)rS(O)2R9xe2x80x2, R9xe2x80x2, and (CH2)rS(O)2NR9dR9xe2x80x2;
R9xe2x80x2, at each occurrence, is independently selected from (CHRxe2x80x2)rC3-6 cycloalkyl substituted with 0-3 R9e, wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, (CHRxe2x80x2)rphenyl substituted with 0-3 R9c, (CHRxe2x80x2)r5-6 membered heterocycle system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c, wherein the heterocycle is selected from oxadiazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxide, thiophene, imidazolyl, pyrrolidinyl, pyrrolyl, thiazolyl, and furanyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R9c;
R9a, at each occurrence, is selected from CN, O-methyl, O-ethyl, CF3, OH, OC(O)-methyl, S-methyl, S-ethyl, S-propyl, S(O)p-methyl, S(O)p-ethyl, S(O)p-propyl, and NR9dR9dxe2x80x2;
R9b, at each occurrence, is selected from cyclopropyl, cyclbutyl, cyclpentyl, CN, CF3, CH2-OC1-5 alkyl, CH2xe2x80x94OH, CH2-SC1-5 alkyl, and CH2xe2x80x94NR9dR9dxe2x80x2;
R9c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rC(O)OC1-5 alkyl, (CH2)rC(O)C1-5 alkyl, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2;
provided that if R9c is attached to a carbon attached to the nitrogen on Ring B, then R9c is selected from (CH2)qOH, (CH2)qOC1-5 alkyl, (CH2)qSC1-5 alkyl, (CH2)qS(O)qC1-5 alkyl, and (CH2)qNR9dR9dxe2x80x2;
R9d and R9dxe2x80x2, at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rC(O)OC1-5 alkyl, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2, or alternatively, two R9e on the same carbon atom form xe2x95x90O; and
R9j, at each occurrence, is selected from cyclpropyl, cyclobutyl, cyclopentyl, CN, CF3, O-methyl, O-ethyl, O-propyl, O-i-propyl, O-butyl, OH, S-methyl, S-ethyl, and NR9dR9dxe2x80x2.
[5] In another embodiment, the present invention provides novel compounds of formula (I-i), wherein: 
Z is selected from O, S, NCN, and NCONH2;
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
[6] In another embodiment, the present invention provides novel compounds of formula (I-ii), wherein: 
Z is selected from O, S, NCN, and NCONH2;
R16, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR16aR16axe2x80x2, NO2, CN, OH, (CH2)rOR16d, (CH2)rC(O)R16b, (CH2)rC(O)NR16aR16axe2x80x2, (CH2)rNR16fC(O)R16b, (CH2)rS(O)pR16b, (CH2)rS(O)2NR16aR16axe2x80x2, (CH2)rNR16fS(O)2R16b, and (CH2)rphenyl substituted with 0-3 R16e;
R16a and R16axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R16e;
R16d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R16e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R16f, at each occurrence, is selected from H, and C1-5 alkyl.
[7] In another embodiment, the present invention provides novel compounds of formula (I-i), wherein:
Ring B is a 5 or 6 membered saturated heterocycle ring, wherein the heterocycle ring is selected from piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1,1-dioxide, tetrahydrothiopyran 1-monooxide, piperidin-2-one, tetrahydropyran-2-one, [1,2]thiazinane 1,1-dioxide, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidin-2-one, dihydrofuran-2-one, and isothiazolidine 1,1-dioxide, the heterocycle ring being optionally substituted by 0-2 R8;
R5 is CH2phenyl substituted with 0-3 R16;
r is selected from 0, 1, and 2.
[8] In another embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
Ring B is a 5 or 6 membered saturated heterocycle ring, wherein the heterocycle ring is selected from piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1,1-dioxide, tetrahydrothiopyran 1-monooxide, piperidin-2-one, tetrahydropyran-2-one, [1,2]thiazinane 1,1-dioxide, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidin-2-one, dihydrofuran-2-one, and isothiazolidine 1,1-dioxide, the heterocycle ring being optionally substituted by 0-2 R8;
R5 is CH2phenyl substituted with 0-3 R16; and
r is selected from 0, 1, and 2.
[9] In another embodiment, the present invention provides novel compounds of formula (I-i), wherein:
J is selected from CH2 and CHR5;
K is selected from CH2 and CHR5;
L is CHR5;
R3 is selected from a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, indazolyl, isoxazolinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rNR15fC(O)O(CHRxe2x80x2)rR15d, (CH2)rOC(O)NR15aR15axe2x80x2, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from tetrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, thiazolyl, pyrazolyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxadiazolyl, and thiadiazolyl;
R15a and R15axe2x80x2, at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
alternatively, R15a and R15axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR15h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl.
[10] In another embodiment, the present invention provides novel compounds of formula (I-ii), wherein:
K is selected from CH2 and CHR5;
L is CHR5;
R3 is selected from a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indazolyl, isoxazolinyl, morpholinyl, pyrrolidinyl, tetrahydropyranyl, tetrahydrofuranyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triaxolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl; and
R15, at each occurrence, is selected from C1-8 alkyl, (CH2)rC3-6 cycloalkyl, CF3, Cl, Br, I, F, (CH2)rNR15aR15axe2x80x2, NO2, CN, OH, (CH2)rOR15d, (CH2)rC(O)R15b, (CH2)rC(O)NR15aR15axe2x80x2, (CH2)rNR15fC(O)R15b, (CH2)rNR15fC(O)O(CHRxe2x80x2)rR15d, (CH2)rOC(O)NR15aR15axe2x80x2, (CH2)rS(O)pR15b, (CH2)rS(O)2NR15aR15axe2x80x2, (CH2)rNR15fS(O)2R15b, (CH2)rphenyl substituted with 0-3 R15e, and a (CH2)r-5-6 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15e, wherein the heterocyclic system is selected from tetrazolyl, piperidinyl, pyrrolidinyl, imidazolyl, thiazolyl, pyrazolyl, pyridyl, thienyl, furanyl, pyrrolyl, oxazolyl, isoxazolyl, triazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, morpholinyl, oxadiazolyl, and thiadiazolyl;
R15a and R15axe2x80x2 at each occurrence, are selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
alternatively, R15a and R15axe2x80x2, along with the N to which they are attached, join to form a 5-6 membered heterocyclic system containing 1-2 heteroatoms selected from NR15h, O, and S and optionally fused with a benzene ring or a 6-membered aromatic heterocycle;
R15b, at each occurrence, is selected from H, C1-6 alkyl, C3-6 cycloalkyl, and (CH2)rphenyl substituted with 0-3 R15e;
R15d, at each occurrence, is selected from C1-6 alkyl and phenyl;
R15e, at each occurrence, is selected from C1-6 alkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, OH, and (CH2)rOC1-5 alkyl; and
R15f, at each occurrence, is selected from H, and C1-5 alkyl
[11] In another embodiment, the present invention provides novel compounds of formula (I), wherein the compound of formula (I) is: 
G is selected from CH2 and Cxe2x95x90O;
L is CHR5;
B is selected from piperidine, tetrahydropyran, tetrahydrothiopyran, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiophene 1-oxide, and tetrahydrothiophene 1,1-dioxide;
R3 is selected from phenyl substituted with 1-2 R15, xe2x80x94CH2xe2x80x94CH2-morpholin-1-yl substituted with 1-2 R15, indazolyl substituted with 1-2 R15, pyrazolyl substituted with 1-2 R15 or thiazolyl substituted with 1-2 R15;
R5 is selected from a CH2-phenyl substituted with 1-2 R16;
R9 is selected from H, C2-6 alkyl substituted with 0-3 R9a, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, neo-pentyl; xe2x80x94CH2CHxe2x95x90CH2; xe2x80x94CH2Cxe2x89xa1CH; 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (CH2)rC(O)C1-6 alkyl substituted with 0-2 R9j, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, t-butyl; C(O)Omethyl, C(O)Ot-butyl, So2methyl, SO2ethyl, SO2propyl, SO2i-propyl, SO2t-butyl, SO2CF3, (CH2)rC(O)NR9dR9dxe2x80x2; (CH2)rC(O)R9xe2x80x2, (CH2)rC(O)NR9dR9xe2x80x2, (CH2)rS(O)2R9xe2x80x2, R9xe2x80x2, and (CH2)rS(O)2NR9dR9xe2x80x2;
R9xe2x80x2, at each occurrence, is independently selected from (CHRxe2x80x2)rC3-6 cycloalkyl, wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, (CHRxe2x80x2)rphenyl substituted with 0-3 R9c, (CHRxe2x80x2)r5-6 membered heterocycle system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c, wherein the heterocycle is selected from oxadiazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxide, thiophene, imidazolyl, pyrrolidinyl, pyrrolyl, thiazolyl, and furanyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R9c;
R9a, at each occurrence, is selected from CN, O-methyl, O-ethyl, CF3, OH, OC(O)-methyl, S-methyl, S-ethyl, S-propyl, S(O)p-methyl, S(O)p-ethyl, S(O)p-propyl, and NR9dR9dxe2x80x2;
R9c, at each occurrence, is selected from methyl, ethyl, propyl, C(O)-methyl, C(O)O-t-butyl;
R9d and R9dxe2x80x2, at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, t-butyl;
R9j, at each occurrence, is selected from O-methyl, O-ethyl, and NR9dR9dxe2x80x2;
R15 is selected from Me, CF3, OMe, OCF3, F, Cl, Br, OH, OMe, C(O)Me, CH(OH)Me, CN, CO2Me, CO2Et, SO2NH2, NHC(O)Me, C(O)NH2, C(O)NHMe, C(O)NHCH2CH2OMe, C(O)piperidinyl, C(O)pyrrolidinyl, C(O)morpholinyl, and a 5-6 membered heterocyclic system, wherein the heterocyclic system is selected from tetrazolyl, indazolyl, pyrazolyl, triazolyl, morpholinyl, and thiazolyl, the heterocyclic system substituted with 0-2 R15e;
R15e is selected from methyl, ethyl, propyl, i-propyl, cyclopropyl, cyclopropylmethyl, acetyl, and t-butoxycarbonyl;
R16 is selected from F, Cl, Br, and I;
[12] In another embodiment, the present invention provides novel compounds of formula (I), wherein the compounds are selected from:
(3R,4R)-4-[3-(3-acetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{1-(2,2-Dimethyl-propionyl)-3-[(3R,4R)-3-((S)-4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{1-Acetyl-3-[(3R,4R)-3-((S)-4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-1-methanesulfonyl-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-1-methyl-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
5-(3-{(3R,4R)-1-tert-butoxycarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester;
5-(3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-urea;
(3R,4S)-3-[3-(3-acetyl-phenyl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3R,4R)-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-3-yl}-urea;
(3R,4R)-4-[3-(3-acetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(3-acetyl-phenyl)-urea;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-urea;
1-(3-acetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-urea;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-isobutyl-piperidin-4-yl}-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
5-(3-{(3R,4R)-1-t-butoxycarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester;
5-(3-{(3S,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-ureido)-indazole-1-carboxylic acid t-butyl ester;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
(3R,4R)-4-[3-(3-acetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
(3S,4R)-4-[3-(3-acetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidin-4-yl}-urea;
(3R,4R)-4-[3-(3-acetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methyl ester;
1-(3-acetyl-phenyl)-3-{(3R,4R)-1-(2,2-dimethyl-propionyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-2-carboxylic acid t-butyl ester;
1-(3-acetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-fluoro-ethyl)-piperidin-4-yl}-urea;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-4-yl}-urea;
1-(3-acetyl-phenyl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-3-yl}-urea;
1-{(3R,4S)-1-Acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(3-acetyl-phenyl)-urea;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(1-methyl-1H-tetrazol-5-yl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-3-(1-methyl-1H-tetrazol-5-yl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-3-(1-methyl-1H-tetrazol-5-yl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-1-(2-oxo-propyl)-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-1-(2-fluoro-ethyl)-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-1-trifluoromethanesulfonyl-piperidin-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-(3-Acetyl-phenyl)-3-{(2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-urea;
1-{(2S,3R)-2-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(2S,3R)-2-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(3-Acetyl-phenyl)-3-{(2S,3R)-2-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-3-yl}-urea;
1-{(2S,3R)-2-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(2S,3R)-2-[(S)-3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-3-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(5-Acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-isobutyryl-piperidin-4-yl}-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-fluoroethyl)-piperidin-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxopropyl)-piperidin-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(3-Acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-4-yl}-urea;
1-{(3R,4R)-3-[(S)3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(3-Acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-4-yl}-urea;
1-{(3R,4R)-3-[(S)3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-4-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)3-(4-Fluoro-benzyl)-piperidine-1-carbonyl]-tetrahydro-pyran-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-[3-(4-fluoro-phenyl)-ureido]-piperidine-1-carboxylic acid t-butyl ester;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-ethyl-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
2-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-[3-(4-fluoro-phenyl)-ureido]-piperidin-1-yl}-N-isopropyl-acetamide;
1-((3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-prop-2-ynyl-piperidin-4-yl)-3-(4-fluoro-phenyl)-urea;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-4-yl}-urea;
1-{(3R,4R)-1xe2x80x2-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-4-yl}-3-(3-acetyl-phenyl)-urea;
1-(3-acetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1xe2x80x2-methyl-[1,4xe2x80x2]bipiperidinyl-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-[3-(3,5-diacetyl-phenyl)-ureido]-piperidine-1-carboxylic acid t-butyl ester;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-ethyl-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-4-yl}-urea;
2-{(3R,4R)-3-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-4-[3-(3,5-diacetyl-phenyl)-ureido]-piperidin-1-yl}-N-isopropyl-acetamide;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-propargyl-piperidin-4-yl}-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid methyl ester;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-5-[3-methylxe2x80x94S-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-ethyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
2-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidin-1-yl}-N-isopropyl-acetamide;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-prop-2-ynyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid t-butyl ester;
1-{(3R,4R)-1-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-4-yl)-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-ethyl-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
2-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidin-1-yl}-N-isopropyl-acetamide;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-prop-2-ynyl-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-4-yl]-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-4-yl}-3-(1-methyl-pyrazol-3-yl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-4-yl}-3-(thiazol-2-yl)-urea;
2-{3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-4-yl]-ureido}-4-methyl-thiazole-5-carboxylic acid ethyl ester;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-(5-acetyl-4-methyl-thiazol-2-yl)-ureido}-piperidine-1-carboxylic acid methyl ester;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid 3-hydroxy-2,2-dimethyl-propyl ester;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-propionyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclopropanecarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclopentanecarbonyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-pyran-4-carbonyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-acetyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-dimethylamino-acetyl)-piperidin-4-yl]-urea;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methylamide;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid dimethylamide;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid ethylamide;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3S,4R)-1-ethyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-propyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-isopropyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclobutyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclopentyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-pyran-4-yl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-thiopyran-4-yl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(1,1-dioxo-hexahydro-1xcex6-thiopyran-4-yl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-4-yl}-urea;
(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-1xe2x80x2-carboxylic acid tert-butyl ester;
1-{(3R,4R)-1xe2x80x2-acetyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-4-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1xe2x80x2-methyl-[1,4xe2x80x2]bipiperidinyl-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclopropylmethyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyclobutylmethyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-benzyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-furan-2-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-furan-3-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiophen-2-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiophen-3-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-imidazol-2-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-imidazol-4-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiazol-2-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxyethyl)-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-2-methylpropyl)-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-3,3,3-trifluoropropyl)-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-ethyl)-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(2-ethoxy-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(2-ethylsulfanyl-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R, 4R)-1-(2-ethanesulfonyl-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(2-acetoxy-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-yl methyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-cyanomethyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(2-diethylamino-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(2-diethylamino-ethyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylethyl]-1-(2-pyrrolidin-1-yl-ethyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-morpholin-1-yl-ethyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-pyrrol-1-yl-ethyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(3-oxo-butyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methyl-3-oxo-butyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(3-hydroxypropyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[(S)-3-hydroxy-2-methylpropyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[(R)-3-hydroxy-2-methylpropyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-(3,3-dimethyl-2-oxo-butyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
2-{(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-1-yl}-N-methyl-acetamide;
2-{(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-1-yl}-N-isopropyl-acetamide;
2-{(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-1-yl}-N-tert-butyl-acetamide;
2-{(3R,4R)-4-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-1-yl}-N,N-dimethyl-acetamide; 1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-cyclopentyl)-piperidin-4-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-1-allyl-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-prop-2-ynyl-piperidin-4-yl}-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(4-fluoro-phenyl)-urea;
1-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-acetyl)-piperidin-3-yl]-3-(4-fluoro-phenyl)-urea;
1-{(3R,4S)-1-cyclopropylmethyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(4-fluoro-phenyl)-urea;
1-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-3-yl]-3-(4-fluoro-phenyl)-urea;
1-(3-acetyl-phenyl)-3-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-acetyl)-piperidin-3-yl]-urea;
1-(3-acetyl-phenyl)-3-{(3R,4S)-1-(2-dimethylamino-acetyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
(3R,4S)-3-[3-(3-acetyl-phenyl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid ethylamide;
1-(3-acetyl-phenyl)-3-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-3-yl]-urea;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-{3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-1-(2,2-dimethyl-propionyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-3-yl]-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-3-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-3-yl]-urea;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[3-(5-methyl-tetrazol-1-yl)-phenyl]-urea;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(1-methyl-pyrazol-3-yl)-urea;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(thiazol-2-yl)-urea;
2-(3-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-ureido)-4-methyl-thiazole-5-carboxylic acid ethyl ester;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methyl ester;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-propionyl-piperidin-3-yl}-urea; 1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methyl-propionyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-(2,2-dimethyl-propionyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-cyclopropanecarbonyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R, 4S)-1cyclobutanecarbonyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-cyclopentanecarbonyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-cyclohexanecarbonyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-pyran-4-carbonyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-acetyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-(2-dimethylamino-acetyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methylamide;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid ethylamide;
(3R, 4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid propylamide;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid isopropylamide;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid allylamide;
(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid (5-acetyl-4-methyl-thiazol-2-yl)-amide;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-3-yl}-urea;
1-{(3R,4S)-1xe2x80x2-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-[1,4xe2x80x2]bipiperidinyl-3-yl}-3-(5-acetyl-4-methyl-thiazol-2-yl)-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1xe2x80x2-methyl-[1,4xe2x80x2]bipiperidinyl-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-cyclopropylmethyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-[(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-pyran-2-ylmethyl)-piperidin-3-yl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-furan-2-ylmethyl-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-furan-3-ylmethyl-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[1,2,4]oxadiazol-3-ylmethyl-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-fluoro-ethyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-(2-ethanesulfonyl-ethyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-1-cyanomethyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-propyl)-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[(S)-2-hydroxy-2-methyl-propyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-[(R)-2-hydroxy-2-methyl-propyl]-piperidin-3-yl}-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-3-yl}-urea;
2-{(3R,4S)-3-[3-(5-acetyl-4-methyl-thiazol-2-yl)-ureido]-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-1-yl}-N,N-dimethyl-acetamide;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-isobutyryl-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-1-benzoyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(propane-2-sulfonyl)-piperidin-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-[3-(2-morpholin-4-yl-ethyl)-ureido]-piperidine-1-carboxylic acid methyl ester;
1-{(3R,4S)-1-acetyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-propionyl-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-1(2,2-dimethyl-propionyl)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-1-cyclobutanecarbonyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(tetrahydro-pyran-4-carbonyl)-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-acetyl)-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-[3-(2-morpholin-4-yl-ethyl)-ureido]-piperidine-1-carboxylic acid dimethylamide;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-[3-(2-morpholin-4-yl-ethyl)-ureido]-piperidine-1-carboxylic acid ethylamide;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methyl-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-1-ethyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-isopropyl-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-1-cyclopropylmethyl-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-oxo-propyl)-piperidin-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-[3-(4-fluoro-phenyl)-ureido]-piperidine-1-carboxylic acid methyl ester;
1-{(3R,4R)-1-(2-dimethylamino-acetyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiazol-2-ylmethyl-piperidin-4-yl}-3-(4-fluoro-phenyl)-urea;
1-[(3R, 4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-(4-fluoro-phenyl)-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-ethyl)-piperidin-4-yl]-3-(4-fluoro-phenyl)-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-3-(4-fluoro-phenyl)-urea;
1-[(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-propyl)-piperidin-4-yl]-3-(4-fluoro-phenyl)-urea;
(3R,4R)-4-[3-(3,5-diacetyl-phenyl)-ureido]-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid methyl ester;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-1-(2-dimethylamino-acetyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl)-urea;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-1-(1,1-dioxo-hexahydro-1xcex6-thiopyran-4-yl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiazol-2-ylmethyl-piperidin-4-yl}-urea;
1-(3,5-diacetyl-phenyl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-4-yl]-urea;
1-(3,5-diacetyl-phenyl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-ethyl)-piperidin-4-yl]-urea;
1-(3,5-diacetyl-phenyl)-3-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-urea;
1-(3,5-diacetyl-phenyl)-3-[(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-propyl)-piperidin-4-yl]-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid methyl ester;
1-{(3R,4R)-1-(2-dimethylamino-acetyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-methylxe2x80x94S-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiazol-2-ylmethyl-piperidin-4-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-ethyl)-piperidin-4-yl]-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-propyl)-piperidin-4-yl]-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-4-{3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-piperidine-1-carboxylic acid methyl ester;
1-{(3R,4R)-1-(2-dimethylamino-acetyl)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-methanesulfonyl-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-thiazol-2-ylmethyl-piperidin-4-yl}-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-methoxy-ethyl)-piperidin-4-yl]-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3R,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-morpholin-4-yl-ethyl)-piperidin-4-yl]-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-[(3S,4R)-3-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-1-(2-hydroxy-propyl)-piperidin-4-yl]-3-[3-bromo-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
(3R,4S)-3-(3-benzyl-ureido)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester;
1-benzyl-3-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-urea;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-[3-(tetrahydro-pyran-4-ylmethyl)-ureido]-piperidine-1-carboxylic acid tert-butyl ester;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-(tetrahydro-pyran-4-ylmethyl)-urea;
(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-3-{3-[2-(tetrahydro-pyran-4-yl)-ethyl]-ureido}-piperidine-1-carboxylic acid tert-butyl ester;
1-{(3R,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-piperidin-3-yl}-3-[2-(tetrahydro-pyran-4-yl)-ethyl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-Fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluoro-benzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl)-3-[5-acetyl-4-methylthiazol-2-yl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-(3-acetylphenyl)-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-tetrahydro-pyran-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-yl}-3-[5-acetyl-4-methylthiazol-2-yl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-yl}-3-[3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-yl}-3-[3-acetylphenyl]-urea;
1-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-1,1-dioxo-tetrahydrothiophen-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
1-(5-acetyl-4-methyl-thiazol-2-yl)-3-{(3R,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-1,1-dioxo-tetrahydro-1xcex6-thiophen-3-yl}-urea;
1-{(3R,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidine-1-carbonyl]-1,1-dioxo-tetrahydrothiophen-3-yl}-3-(2-morpholin-4-yl-ethyl)-urea;
(3S,4S)-3-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-4-{3-[3-methyl-5-(1-methyl-1H-tetrazol-5-yl)-phenyl]-ureido}-pyrrolidine-1-carboxylic acid tert-butyl ester;
1-(5-acetyl-4-methylthiazol-2-yl)-3-{(3S,4S)-4-[(S)-3-(4-fluorobenzyl)-piperidin-1-ylmethyl]-pyrrolidin-3-yl}-urea.
In another embodiment, the present invention provides a pharmaceutical composition, comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for modulation of chemokine receptor activity comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention.
In another embodiment, the present invention provides a method for treating inflammatory disorders comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the present invention
In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, inflammatory bowel diseases, idiopathic pulmonary fibrosis, bullous pemphigoid, helminthic parasitic infections, allergic colitis, eczema, conjunctivitis, transplantation, familial eosinophilia, eosinophilic cellulitis, eosinophilic pneumonias, eosinophilic fasciitis, eosinophilic gastroenteritis, drug induced eosinophilia, HIV infection, cystic fibrosis, Churg-Strauss syndrome, lymphoma, Hodgkin""s disease, and colonic carcinoma.
In another embodiment, the present invention provides a method for treating or preventing disorders selected from asthma, allergic rhinitis, atopic dermatitis, and inflammatory bowel diseases.
In another embodiment, the present invention provides a method for treating or preventing asthma.
In another embodiment, the compound of Formula (I) is 
In another embodiment, the compound of Formula (I) is 
In another embodiment, J is CH2, K is selected from CH2 and CHR5, and L is selected from CH2 and CHR5, wherein at least one of K or L contains an R5.
In another embodiment, K is CH2.
In another embodiment, L is CH2.
In another embodiment, Z is selected from O, S, NCN, an d NCONH2.
In another embodiment, E is 
In another embodiment, E is 
In another embodiment, Ring B is piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1,1-dioxide, piperidin-2-one, tetrahydropyran-2-one, [1,2]thiazinane 1,1-dioxide, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidin-2-one, dihydrofuran-2-one, and isothiazolidine 1,1-dioxide.
In another embodiment, Ring B is piperidine, tetrahydropyran, tetrahydrothiopyran, tetrahydrothiopyran 1,1-dioxide, piperidin-2-one, tetrahydropyran-2-one, [1,2]thiazinane 1,1-dioxide, pyrrolidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidin-2-one, dihydrofuran-2-one, and isothiazolidine 1,1-dioxide.
In another embodiment, Ring B is piperidine and tetrahydropyran.
In another embodiment, R1 and R2 are H.
In another embodiment, R3 is selected from a (CR3xe2x80x2H)r-carbocyclic residue substituted with 0-5 R15, wherein the carbocyclic residue is selected from phenyl, C3-6 cycloalkyl, naphthyl, and adamantyl; and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R3 is selected from a methyl substituted with 0-2 R10, C2-8 alkyl substituted with 0-2 R7, a C3-10 carbocyclic residue substituted with 0-3 R15, wherein the carbocyclic residue is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, naphthyl and adamantyl, and a (CR3xe2x80x2H)r-heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R3 is selected from a phenyl substituted with 0-2 R15; and a (CH2)r-5-10 membered heterocyclic system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-2 R15, wherein the heterocyclic system is selected from pyridinyl, morpholinyl, pyrazolyl, indazolyl, thiazolyl and r is 0, 1, or 2.
In another embodiment, R5 is selected from (CR5xe2x80x2H)t-phenyl substituted with 0-5 R16; and a (CR5xe2x80x2H)t-heterocyclic system substituted with 0-3 R16, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R5 is selected from a CH2xe2x80x94C3-10 carbocyclic residue substituted with 1-5 R16 and a heterocyclic system substituted with 0-3 R15, wherein the heterocyclic system is selected from pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiophenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, indolinyl, isoindolyl, isothiadiazolyl, isoxazolyl, piperidinyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiadiazolyl, thiazolyl, oxazolyl, pyrazinyl, and pyrimidinyl.
In another embodiment, R5 is CH2-phenyl substituted with 0-3 R16.
In another embodiment, R9 is selected from H, CH3, C2-6 alkyl substituted with 0-3 R9a, C3-8 alkenyl, C3-8 alkynyl, C1-3haloalkyl, (CH2)rC(O)C1-6 alkyl substituted with 0-2 R9j, (CH2)rC(O)OC1-6 alkyl substituted with 0-3 R9b, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rS(O)2C1-6 alkyl, S(O)2C1-6 trifluoromethyl, (CH2)rC(O)R9xe2x80x2, (CH2)rC(O)NR9dR9xe2x80x2, (CH2)rS(O)2R9xe2x80x2, R9xe2x80x2, and (CH2)rS(O)2NR9dR9xe2x80x2;
R9xe2x80x2, at each occurrence, is independently selected from (CHRxe2x80x2)rC3-6 cycloalkyl substituted with 0-3 R9e, wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, (CHRxe2x80x2)rphenyl substituted with 0-3 R9c, (CHRxe2x80x2)r5-6 membered heterocycle system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c, wherein the heterocycle is selected from oxadiazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxide, thiophene, imidazolyl, pyrrolidinyl, pyrrolyl, thiazolyl, and furanyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R9c;
R9a, at each occurrence, is selected from CN, O-methyl, O-ethyl, CF3, OH, OC(O)-methyl, S-methyl, S-ethyl, S-propyl, S(O)p-methyl, S(O)p-ethyl, S(O)p-propyl, and NR9dR9dxe2x80x2;
R9b, at each occurrence, is selected from cyclopropyl, cyclbutyl, cyclpentyl, CN, CF3, CH2-OC1-5 alkyl, CH2-OH, CH2-SC1-5 alkyl, and CH2-NR9dR9dxe2x80x2;
R9c, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rC(O)OC1-5 alkyl, (CH2)rC(O)C1-5 alkyl, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2;
provided that if R9c is attached to a carbon attached to the nitrogen on Ring B, then R9c is selected from (CH2)qOH, (CH2)qOC1-5 alkyl, (CH2)qSC1-5 alkyl, (CH2)qS(O)qC1-5 alkyl, and (CH2)qNR9dR9dxe2x80x2;
R9d and R9dxe2x80x2, at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and phenyl;
R9e, at each occurrence, is selected from C1-6 alkyl, C3-6 cycloalkyl, Cl, F, Br, I, CN, NO2, (CF2)rCF3, (CH2)rOC1-5 alkyl, (CH2)rC(O)OC1-5 alkyl, (CH2)rC(O)NR9dR9dxe2x80x2, (CH2)rOH, (CH2)rSC1-5 alkyl, (CH2)rS(O)pC1-5 alkyl, and (CH2)rNR9dR9dxe2x80x2, or alternatively, two R9e on the same carbon atom form xe2x95x90O; and
R9j, at each occurrence, is selected from cyclpropyl, cyclobutyl, cyclopentyl, CN, CF3, O-methyl, O-ethyl, O-propyl, O-i-propyl, O-butyl, OH, S-methyl, S-ethyl, and NR9dR9dxe2x80x2.
In another embodiment, R9 is selected from H, C2-6 alkyl substituted with 0-3 R9a, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, i-butyl, s-butyl, t-butyl, neo-pentyl; xe2x80x94CH2CHxe2x95x90CH2; xe2x80x94CH2Cxe2x89xa1CH; 2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, (CH2)rC(O)C1-6 alkyl substituted with 0-2 R9j, wherein the alkyl is selected from methyl, ethyl, propyl, i-propyl, butyl, t-butyl; C(O)Omethyl, C(O)Ot-butyl, SO2methyl, SO2ethyl, SO2propyl, SO2i-propyl, SO2t-butyl, SO2CF3, (CH2)rC(O)NR9dR9dxe2x80x2; (CH2)rC(O)R9xe2x80x2, (CH2)rC(O)NR9dR9xe2x80x2, (CH2)rS(O)2R9xe2x80x2, R9xe2x80x2, and (CH2)rS(O)2NR9dR9xe2x80x2;
R9xe2x80x2, at each occurrence, is independently selected from (CHRxe2x80x2)rC3-6 cycloalkyl, wherein the cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, (CHRxe2x80x2)rphenyl substituted with 0-3 R9c, (CHRxe2x80x2)r5-6 membered heterocycle system containing 1-4 heteroatoms selected from N, O, and S, substituted with 0-3 R9c, wherein the heterocycle is selected from oxadiazolyl, morpholinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrothiopyranyl dioxide, thiophene, imidazolyl, pyrrolidinyl, pyrrolyl, thiazolyl, and furanyl, and (CHRxe2x80x2)rphenyl substituted with 0-3 R9c;
R9a, at each occurrence, is selected from CN, O-methyl, O-ethyl, CF3, OH, OC(O)-methyl, S-methyl, S-ethyl, S-propyl, S(O)p-methyl, S(O)p-ethyl, S(O)p-propyl, and NR9dR9dxe2x80x2;
R9c, at each occurrence, is selected from methyl, ethyl, propyl, C(O)-methyl, C(O)O-t-butyl;
R9d and R9dxe2x80x2, at each occurrence, are independently selected from H, methyl, ethyl, propyl, i-propyl, butyl, t-butyl;
R9j, at each occurrence, is selected from O-methyl, O-ethyl, and NR9dR9dxe2x80x2.
The invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof. This invention also encompasses all combinations of preferred aspects of the invention noted herein. It is understood that any and all embodiments of the present invention may be taken in conjunction with any other embodiment to describe additional even more preferred embodiments of the present invention. Furthermore, any elements of an embodiment are meant to be combined with any and all other elements from any of the embodiments to describe additional embodiments.
The compounds herein described may have asymmetric centers. Compounds of the present invention containing an asymmetrically substituted atom may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomeric form is specifically indicated.
The term xe2x80x9csubstituted,xe2x80x9d as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
When any variable (e.g., Ra) occurs more than one time in any constituent or formula for a compound, its definition at each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 Ra, then said group may optionally be substituted with up to two Ra groups and Ra at each occurrence is selected independently from the definition of Ra. Also, combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
When a bond to a substituent is shown to cross a bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of a given formula, then such substituent may be bonded via any atom in such substituent. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
As used herein, xe2x80x9cC1-8 alkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, examples of which include, but are not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, sec-butyl, t-butyl, pentyl, and hexyl. C1-8 alkyl, is intended to include C1, C2, C3, C4, C5, C6, C7, and C8 alkyl groups. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. xe2x80x9cAlkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl, and the like. xe2x80x9cC3-6 cycloalkylxe2x80x9d is intended to include saturated ring groups having the specified number of carbon atoms in the ring, including mono-, bi-, or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl in the case of C7 cycloalkyl. C3-6 cycloalkyl, is intended to include C3, C4, C5, and C6 cycloalkyl groups
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo, and iodo; and xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups, for example CF3, having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)).
As used herein, the term xe2x80x9c5-6-membered cyclic ketalxe2x80x9d is intended to mean 2,2-disubstituted 1,3-dioxolane or 2,2-disubstituted 1,3-dioxane and their derivatives.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocycles include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, cyclooctyl,; [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclic systemxe2x80x9d or xe2x80x9cheterocyclic ringxe2x80x9d is intended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or 7, 8, 9, or 10-membered bicyclic heterocyclic ring which is saturated, partially unsaturated or unsaturated (aromatic), and which consists of carbon atoms and 1, 2, 3, or 4 heteroatoms independently selected from the group consisting of N, NH, O and S and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The nitrogen and sulfur heteroatoms may optionally be oxidized. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. If specifically noted, a nitrogen in the heterocycle may optionally be quaternized. It is preferred that when the total number of S and O atoms in the heterocycle exceeds 1, then these heteroatoms are not adjacent to one another. As used herein, the term xe2x80x9caromatic heterocyclic systemxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic aromatic ring which consists of carbon atoms and from 1 to 4 heterotams independently selected from the group consisting of N, O and S.
Examples of heterocycles include, but are not limited to, 1H-indazole, 2-pyrrolidonyl, 2H,6H-1,5,2-dithiazinyl, 2H-pyrrolyl, 3H-indolyl, 4-piperidonyl, 4aH-carbazole, 4H-quinolizinyl, 6H-1,2,5-thiadiazinyl, acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalonyl, carbazolyl, 4aH-carbazolyl, xcex2-carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuran-2-one, dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl, indolizinyl, indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolidine 1,1-dioxide, isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinylperimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidin-2-one, piperidinyl, pteridinyl, piperidonyl, 4-piperidonyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl, pyrrolidin-2-one, pyrrolidinyl, pyrrolinyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl (THP), tetrahydroquinolinyl, tetrahydropyran-2-one, tetrahydrothiophenyl, 1-oxo-hexahydro-1xcex4-thiopyranyl, 1,1-dioxo-hexahydro-1xcex6-thiopyranyl, tetrahydrothiopyranyl (THTP), 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, 1,1-dioxo-1xcex6-[1,2]thiazinanyl, thiazolyl, thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, tetrazolyl, and xanthenyl. Preferred heterocycles include, but are not limited to, pyridinyl, thiophenyl, furanyl, indazolyl, benzothiazolyl, benzimidazolyl, benzothiaphenyl, benzofuranyl, benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, imidazolyl, indolyl, isoidolyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl, pyrrazolyl, 1,2,4-triazolyl, 1,2,3-triazolyl, tetrazolyl, thiazolyl, oxazolyl, pyrazinyl, pyrimidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, 1-oxo-hexahydro-1xcex4-thiopyranyl, 1,l-dioxo-hexahydro-1xcex6-thiopyranyl, piperidin-2-one, tetrahydropyran-2-one, 1,1-dioxo-1xcex6-[1,2]thiazinanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidin-2-one, dihydrofuran-2-one, and isothiazolidine 1,1-dioxide. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
The phrase xe2x80x9cpharmaceutically acceptablexe2x80x9d is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
Since prodrugs are known to enhance numerous desirable qualities of pharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc . . . ) the compounds of the present invention may be delivered in prodrug form. Thus, the present invention is intended to cover prodrugs of the presently claimed compounds, methods of delivering the same and compositions containing the same. xe2x80x9cProdrugsxe2x80x9d are intended to include any covalently bonded carriers which release an active parent drug of the present invention in vivo when such prodrug is administered to a mammalian subject. Prodrugs the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy, amino, or sulfhydryl group is bonded to any group that, when the prodrug of the present invention is administered to a mammalian subject, it cleaves to form a free hydroxyl, free amino, or free sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of the present invention.
As used herein, xe2x80x9ctreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d cover the treatment of a disease-state in a mammal, particularly in a human, and include: (a) preventing the disease-state from occurring in a mammal, in particular, when such mammal is predisposed to the disease-state but has not yet been diagnosed as having it; (b) inhibiting the disease-state, i.e., arresting it development; and/or (c) relieving the disease-state, i.e., causing regression of the disease state.
xe2x80x9cStable compoundxe2x80x9d and xe2x80x9cstable structurexe2x80x9d are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The compounds of Formula I can be prepared using the reactions and techniques described below. The reactions are performed in a solvent appropriate to the reagents and materials employed and suitable for the transformations being effected. It will be understood by those skilled in the art of organic synthesis that the functionality present on the molecule should be consistent with the transformations proposed. This will sometimes require a judgment to modify the order of the synthetic steps or to select one particular process scheme over another in order to obtain a desired compound of the invention. It will also be recognized that another major consideration in the planning of any synthetic route in this field is the judicious choice of the protecting group used for protection of the reactive functional groups present in the compounds described in this invention. An authoritative account describing the many alternatives to the trained practitioner is Greene and Wuts (Protective Groups In Organic Synthesis, Wiley and Sons, 1999).
Generally, compounds described in the scope of this patent application can be synthesized by the route described in Schemes 1, 2 or 3. In all schemes, P is a suitable protecting group as described in Greene and Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley and Sons, New York. In Scheme 1, the appropriately substituted pyrrolidine (n=0) or piperidine (n=1) 1 is alkylated by a N-protected alkylhalide (halide=Cl, Br, I), mesylate, tosylate or triflate, 2, (where E represents a linkage described within the scope of this application in its fully elaborated form with the appropriate protecting groups as understood by one skilled in the art or in a precursor form which can be later elaborated into its final form by methods familiar to one skilled in the art) with or without base or an acid scavenger to yield the piperidinyl- or pyrrolidinylalkyl protected amine 3. If the halide is not I, then KI can also be added to facilitate the displacement, provided the solvent is suitable, such as an alcohol, 2-butanone, DMF or DMSO, amongst others. The displacement can be performed at room temperature to the reflux temperature of the solvent. The protecting group is subsequently removed to yield amine 4. Protecting groups include phthalimide which can be removed by hydrazine, a reaction familiar to one skilled in the art; bis-BOC which can be removed by either TFA or HCl dissolved in a suitable solvent, both procedures being familiar to one skilled in the art; a nitro group instead of an amine which can be reduced to yield an amine by conditions familiar to one skilled in the art; 2,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyl-disilylazacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and other protecting groups. Reaction with an isocyanate or isothiocyanate 5 (Zxe2x95x90O, S) yields urea or thiourea 6. Reaction with a chloroformate or chlorothioformate 7 (Zxe2x95x90O,S) such as o-, p-nitrophenyl-chloroformate or phenylchloroformate (or their thiocarbonyl equivalents), followed by displacement with an amine 9, also yields the corresponding urea or thiourea 6. Likewise, reaction of carbamate 8 (Xxe2x95x90H, or 2- or 4-NO2) with disubstituted amine 10 yields trisubstituted urea or thiourea 12. Reaction of the amine 4 with an N,N-disubstituted carbamoyl chloride 11 (or its thiocarbonyl equivalent) yields the corresponding N,N-disubstituted urea or thiourea 12. Amine 4 can also be reductively aminated with aldehyde 13 to yield 14 by conditions familiar to one skilled in the art and by the following conditions: Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598. This secondary amine can subsequently be reacted with isocyanates or isothiocyanates to yield trisubstituted ureas 15 or with carbamoyl chlorides to yield tetrasubstituted ureas 16.
One can also convert amine 4 into an isocyanate, isothiocyanate, carbamoyl chloride or its thiocarbonyl equivalent (isocyanate: Nowakowski, J. J Prakt. Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J. et al., Angew. Chem. 1995, 107 (22), 2746-2749; Nowick, J. S.et al., J. Org. Chem. 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73; isothiocyanate: Strekowski L.et al., J. Heterocycl. Chem. 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett. 1997, (3), 289-290) carbamoyl chloride: Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218; thiocarbamoyl chloride: Ried, W.; Hillenbrand, H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590) (these reactions are not shown in Scheme 1). These isocyanates, isothiocyanates, carbamoyl chlorides or thiocarbamoyl chlorides can then be reacted with R2R3NH to yield di- or trisubstituted ureas or thioureas 12. An additional urea forming reaction involves the reaction of carbonyldiimidazole (CDI) (Romine, J. L.; Martin, S. W.; Meanwell, N. A.; Epperson, J. R.; Synthesis 1994 (8), 846-850) with 4 followed by reaction of the intermediate imidazolide with 9 or in the reversed sequence (9+CDI, followed by 4). Activation of imidazolide intermediates also facilitates urea formation (Bailey, R. A., et al., Tet. Lett. 1998, 39, 6267-6270). One can also use 14 and 10 with CDI. The urea forming reactions are done in an aprotic inert solvent such as THF, toluene, DMF, etc., at room temperature to the reflux temperature of the solvent and can employ the use of an acid scavenger or base when necessary such as carbonate and bicarbonate salts, triethylamine, DBU, Hunig""s base, DMAP, etc.
Scheme 2 describes the synthesis of compounds with an carbonyl linking the appropriately substituted pyrrolidine (n=0) or piperidine (n=1) 1 and B. When carboxylic acid 17 is used, a wide variety of dehydrating coupling reagents may be used to prepare the amide 198 from amine 1. A review of the possible reaction conditions was prepared by Y. S. Klausner and M. Bodansky in Synthesis 1972, 9, 453-463. Additional references by E. Gross and J. Meienhofer can be found in the monograph series The Peptides, 4 vols.; Academic Press: New York, 1979-1983. Alternatively the acid chloride 18 can be prepared from carboxylic acid 17 via thionyl chloride or oxalyl chloride among other reagents (see Ansell in S. Patai, The Chemistry of Carboxylic Acids and Esters, Wiley Interscience: New York 1969, 35-68) and then coupled with amine 1 to give amide 19. Deprotection of amide 19 gives the required intermediate amine 20, which can be further elaborated to the final products by the procedures outlined in Scheme 1.
An alternative coupling of a alkyl linkage to the appropriately substituted pyrrolidine (n=0) or piperidine (n=1) 1 and B uses an reductive amination sequence (Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598) shown in Scheme 3. The appropriately protected aldehyde 21 is reacted with amine 1 and the resulting imine is reduced with sodium triacetoxy-borohyride. Alternative hydride sources such as sodium cyanoborohydride may also be used. Deprotection of protected amine 22 gives the required intermediate amine 23, which can be further elaborated to the final products by the procedures outlined in Scheme 1.
Substituted pyrrolidines and piperidines 1 can either be obtained commercially or be prepared as shown in the example of Scheme 4. Commercially available N-benzylpiperid-3-one 24 can be debenzylated and protected with a BOC group employing reactions familiar to one skilled in the art. Subsequent Wittig reaction followed by reduction and deprotection yields piperidine 28 employing reactions familiar to one skilled in the art. Substituted pyrrolidines may be made by a similar reaction sequence. Other isomers and analogs around the piperidine ring can also be made by a similar reaction sequence. Chiral pyrrolidines/piperidines can be synthesized via asymmetric hydrogenation of 18 using chiral catalysts (see Parshall, G. W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J. P., Hegedus, L. S. Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, Calif., 1980, pp. 341-348). 
Guanidines (Zxe2x95x90NR1a) can be synthesized by the methods outlined in Scheme 5. Compound 29 where Zxe2x95x90S can be methylated to yield the methylisothiourea 30. Displacement of the SMe group with amines yields substituted guanidines 31 (see H. King and I. M. Tonkin J. Chem. Soc. 1946, 1063 and references therein). Alternatively, reaction of thiourea 29 with amines in the presence of triethanolamine and xe2x80x9clac sulfurxe2x80x9d which facilitates the removal of H2S yields substituted guanidines 31 (K. Ramadas, Tet. Lett. 1996, 37, 5161 and references therein). Finally, the use of carbonimidoyldichloride 32, or 33 followed by sequential displacements by amines yields the corresponding substituted guanidine 31 (S. Nagarajan, et al., Syn. Comm. 1992, 22, 1191-8 and references therein). In a similar manner, carbonimidoyldichlorides, R2xe2x80x94Nxe2x95x90C(Cl)2 (not shown in Scheme 5) and R3xe2x80x94Nxe2x95x90C(Cl)2 (not shown) can also be reacted sequentially with amines to yield di- and trisubstituted guanidine 23.
Schemes 6 through 30 and Scheme 43 describe the syntheses of the variety of heterocyclic linkers, B. The protecting groups shown in the following schemes were chosen to maximize the utility of intermediates in a variety of schemes and may be interchanged with other compatible groups. While the synthesis of only one enantiomer is shown, the chiral precursors are available in both forms and therefore any isomer can be made from commercially available starting materials.
Scheme 6 describes the preparation of 2,3-disubstituted piperidines. The aspartic acid 34 can be exhaustively protected with benzyl bromide and the beta-carbon can be alkylated with allyl bromide to give the amino ester 35 as a mixture of diastereomers. Hydroboration can provide the alcohol 36 (H. C. Brown, J. C. Chen; J. Org. Chem. 1981, 46, 3978), with can be oxidized to an aldehyde (K. Omura, D. Swerm; Tet. Lett. 1978, 34, 1651) and the benzyl groups removed by catalytic hydrogenation. The intermediate aminoaldehyde cyclizes to an imine which can be further reduced to an aminoacid. Coupling this aminoacid with BOP-Cl (Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tet. Lett. 1975, 14, 1219) and the corresponding cyclic amine can give amide 37. Acidic hydrolysis of the ester, Boc protection of the amine, Curtius rearrangement via dppa (Deng, J.; Hamada, Y.; Shioiri, T. Tet. Lett. 1996, 37, 2261) can provide the amine 38. To prepare the methylene derivative, borane reduction of amine 38 can give amine 39.
For the synthesis of 3,4-disubstituted piperidines, the sequence shown in Scheme 7 can be used. Following a procedure using an analog of a cyclohexanone derivative (Hayashi, Y.; Rohde, J. J.; Corey, E. J. J. Am. Chem. Soc. 1996, 118(23), 5502), the imine of 4-ketopiperidine 40 can be prepared by heating with (R)-alpha-methyl benzylamine with Dean-Stark trapping. Reduction with sodium triacetoxyborohyride can give the cis-amino ester 42. Epimerization can give the trans derivative 43. Hydrogenolysis of the benzyl group and protection as a benzyl carbamate 44 can provide a common intermediate for the hydrolysis and coupling to prepare amide 45 after deprotection. Alternatively, the ester can reduced to an alcohol, oxidized to an aldehyde, reductively aminated and deprotected to give amine 46.
In a very similar manner, ketopiperidine 47 can be converted to amide 52 or amine 53 as shown in Scheme 8.
The synthesis of 2,3-disubstituted dihydropyrans is described in Scheme 9. Starting with diol 54, mono-protection and oxidation (Siedlecka, R.; Skarzewski, J. k; Mlochowski, J.; Tet. Lett. 1990, 31(15), 2177) can give acid 55. Acylation of the chiral auxiliary mediated by pivaloyl chloride can give oxazolinone 57. Sparteine-mediated aldol condensation with cinnamaldehyde sets up the required stereochemistry in alcohol 58 (Crimmins, M. T.; King, B. W.; Tabet, E. A.; J. Am. Chem. Soc. 1997, 119(33), 7883). Fluoride deprotection, triflate-mediated cyclization and lithium peroxide removal of the auxiliary can provide dihydropyran 59. Curtius rearrangement in the presence of t-butanol can produce the required protected amine. Oxidation with ozone and quenching with dimethyl sulfide can give the aldehyde 61. Oxidation of aldehyde 61 with TEMPO can give carboxylic acid 60.
Scheme 10 describes the synthesis of 3,4-disubstituted dihydropyrans. Coupling of oxazolinone 56 with cinnamoyl chloride and subsequent boron-mediated aldol condensation (Galatsis, P.; Millan, S. D.; Ferguson, G.; J. Org. Chem. 1997, 62(15), 5048) with aldehyde 62 can give alcohol 63. Lithium borohydride auxiliary removal, protection of the primary alcohol with TBSCl, mesylate formation of the secondary alcohol, displacement of the mesylate with azide and reduction of the azide and protection of the resulting amine can give 64. Ozonolysis followed by reductive workup, mesylate formation of the alcohol, selective fluoride deprotection of the TBMP silyl ether (Guindon, Y.; Fortin, R.; Yaokim, C.; Gillard, J. W.; Tet. Lett. 1984, 25, 4717), and basic cyclization can provide dihydropyran 65. Fluoride deprotection followed by Swern oxidation can produce aldehyde 66 for reductive amination. Alternatively, the alcohol can be oxidized with PDC (Corey, E. J.; Schmidt, G. Tet. Lett. 1979, 5, 399) to acid 67.
The preparation of the regioisomeric 3,4-disubstituted dihydropyrans is shown in Scheme 11. One of the key differences between Schemes 11 and 10 is the aldol reaction with the shorter chain aldehyde 68. Instead of ozonolysis, the olefin 70 can be hydroborated, the resulting alcohol can be mesylated, and, after deprotection, undergoes ring closure to give the desired dihydropyran 71. Oxidation can give either 72 or 73.
For the corresponding dihydrothiopyrans, advanced precursors from the dihydropyran syntheses were used.
Scheme 12 describes the synthesis of 2,3-disubstituted dihydrothiopyrans. Starting with alcohol 58, Lawesson""reagent displaces the hydroxyl with retention of configuration (Eberle, M. K.; Nuninger, F.; Weber, H-P.; J. Org. Chem. 1995, 60(8), 2610). Acidic fluoride deprotection removes the silyl group and catalyzes the cyclization to the dihydrothiopyran. Lithium hydroperoxide removes the chiral auxiliary and oxidizes the sulfur to the sulfone 74. Curtius rearrangement with Boc anhydride and ozonolysis with oxidative workup can give acid 75. Ozonolysis with reductive workup can give aldehyde 76.
The preparation of the regioisomeric dihydrothiopyrans can be shown in Scheme 13. Ozonolysis of olefin 64 with reductive workup can provide an alcohol. Selective fluoride deprotection of the TBMP silyl group (discussed with scheme 10), mesylate formation on both alcohols, followed by displacement with sodium sulfide and subsequent ring closure can give sulfide 77. Fluoride deprotection and Swern oxidation can give aldehyde 78. Alternatively, PDC oxidation (Jeong, L. S.; Schinazi, R. F.; Beach, J. W.; Kim, H. O.; Shanmuganathan, K.; J. Med. Chem. 1993, 36(18), 2627) can give acid 79.
The preparation of the other regioisomeric dihydrothiopyrans can be shown in Scheme 14. Selective fluoride deprotection of the TBMP silyl group on 70 (discussed previously), mesylate formation, can be followed by displacement of the mesylate with sodium sulfide. Reduction of the olefin initiates ring closure to give sulfide 80 (Aggarwal, V. K.; Ford, J. G.; Fonquerna, S.; Adams, H.; Jones, R. V. H.; Fieldhouse, R.; J. Am. Chem. Soc. 1998, 120, 30). Fluoride deprotection and Swern oxidation can give aldehyde 81. Alternatively, PDC oxidation can give acid 82.
Scheme 15 shows the synthesis of the 5,6-disubstituted lactams. Alcohol 36 can be oxidized with PDC to the carboxylic acid, the ester and amine are deprotected by hydrogenolysis, heat can be applied to do a intramolecular cyclization, and the remaining carboxylic acid can be coupled with BOP-Cl with the amine 1 to give amide 83. Acidic ester hydrolysis with trifluoroacetic acid followed by Curtius rearrangement with dppa can provide amine 84.
If the methylene linker can be desired for the 5,6-disubstituted lactams, then the synthesis can be outlined in Scheme 16. Alcohol 36 can be oxidized with PDC to the carboxylic acid, the ester and amine are deprotected by hydrogenolysis, heat can be applied to do a intramolecular cyclization, and the remaining carboxylic acid can be converted to the acid chloride, reduced to the alcohol and protected with the TBDP silyl group to give ester 85. Acidic ester hydrolysis with trifluoroacetic acid, Curtius rearrangement with dppa and Boc protection of the amine, fluoride deprotection and Swern oxidation can provide aldehyde 86.
Scheme 17 describes the synthesis of 3,4-disubstituted lactams. Olefin 64 can be ozonolyzed with an oxidative workup. The resulting carboxylic acid can be converted to methyl ester 87 with trimethylsilyl diazomethane. Selective fluoride deprotection, mesylate formation, azide displacement of the mesylate, reduction of the azide and concomitant cyclization onto the ester can provide amide 88. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 89.
Scheme 18 describes the synthesis of 4,5-disubstituted lactams. Ether 64 can be selectively deprotected, oxidized to a carboxylic acid and esterified with trimethylsilyl diazomethane to give ester 90. Ozonolysis of the olefin with reductive workup, followed by mesylate formation of the resulting alcohol, azide displacement of the mesylate, reduction of the azide and concomitant cyclization onto the ester can provide amide 91. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 92. Alternatively, oxidation with PDC can give acid 93.
Scheme 19 describes the synthesis of regioisomeric 4,5-disubstituted lactams. Olefin 70 can be hydroborated, the resulting alcohol can be oxidized to a carboxylic acid and esterified with trimethylsilyl diazomethane to give ester 94. Selective fluoride deprotection, followed by mesylate formation of the resulting alcohol, azide displacement of the mesylate, reduction of the azide and concomitant cyclization onto the ester can provide amide 95. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 96. Alternatively, oxidation with PDC can give acid 97.
Scheme 20 describes the synthesis of regioisomeric 2,3-disubstituted lactams. Ether 70 can be selectively deprotected, the resulting alcohol can be oxidized to a carboxylic acid and esterified with trimethylsilyl diazomethane to give ester 98. Hydroboration, followed by mesylate formation of the resulting alcohol, azide displacement of the mesylate, reduction of the azide and concomitant cyclization onto the ester can provide amide 99. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 100. Alternatively, oxidation with PDC can give acid 101.
The corresponding lactones are prepared in a series of synthetic schemes that parallel those used to prepare the corresponding lactams. The synthesis of 5,6-disubstituted lactones is described in Scheme 21. Starting with ether 58, fluoride deprotection, selective oxidation of the primary alcohol with quinolinium chlorochromate (Singh, J.; Kalsi, Partap S.; Jawanda, G. S.; Chhabra, B. R.; Chem. Ind. 1986, 21, 751), further oxidation of the resulting aldehyde with silver(II) oxide (Corey, E. J.; Gilman, N. W.; Ganem, B. E.; J. Amer. Chem. Soc. 1968, 90(20), 5616), heating to facilitate cyclization, and lithium peroxide cleavage of the auxiliary can provide lactone 102. Curtius rearrangement followed by ozonolysis with a reductive workup give aldehyde 103. Alternatively, an oxidative workup can give acid 104.
Scheme 22 describes the synthesis of 3,4-disubstituted lactones. Olefin 64 can be ozonolyzed with an oxidative workup. The TBMP silyl group can be selectively removed with fluoride, the alcohol can be heated and cyclizes with the carboxylic acid to give the lactone 105. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 106.
Scheme 23 describes the synthesis of 3,4-disubstituted lactones. The TBMP silyl group of ether 64 can be selectively removed with fluoride, the alcohol can be oxidized with PDC to a carboxylic acid, and the olefin can be ozonolyzed with an reductive workup to facilitate closure to the lactone 107. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 108. Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 109.
Scheme 24 describes the synthesis of regioisomeric 4,5-disubstituted lactones. Olefin 70 can be hydroborated, the resulting alcohol can be oxidized to a carboxylic acid, the TBMP silyl can be selectively deprotected, and heated to promote cyclization to give amide 110. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 111. Alternatively, oxidation with PDC can give acid 112.
Scheme 25 describes the synthesis of regioisomeric 3,4-disubstituted lactones. The TBMP silyl group of ether 70 can be selectively removed with fluoride, the alcohol can be oxidized with PDC to a carboxylic acid, and the olefin can be hydroborated and heated to facilitate closure to the lactone 113. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 114. Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 115.
Scheme 26 shows the synthesis of the 5,6-disubstituted sulfonamides. Alcohol 36 can be converted to the thiol with Lawesson""s reagent (Nishio, T.; J. Org. Chem. 1997, 62(4), 1106), the thiol can be oxidized with performic acid (Roberts, d. V.; J. biol. Chem. 1953, 204, 871), the benzyl groups were hydrogenolyzed and the mixture heated to facilitate cyclization to sulfonamide 116 (Selve, C.; Neiedercorn, F.; Nacro, M.; Castro, B.; Gabriel, M.; Tetrahedron 1981, 37, 1903). The carboxylic acid can be converted to the acid chloride with oxalyl chloride, reduced with sodium borohyride, and protected as a TBDP silyl ether 117. Acidic ester hydrolysis, Curtius rearrangement with dppa, fluoride deprotection, followed by Swern oxidation can provide aldehyde 118.Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 119.
Scheme 27 describes the synthesis of 3,4-disubstituted sulfonamides. The olefin 64 can be ozonolyzed with reductive workup, the resulting alcohol can be converted to a thiol, and then oxidized to the sulfonic acid 120. Selective fluoride deprotection, mesylate formation, azide displacement and hydrogenation followed by cyclization can provide sulfonamide 121. Fluoride deprotection and Swern oxidation can give aldehyde 122.
Scheme 28 describes the synthesis of 4,5-disubstituted sulfonamides. The ether 64 can be selectively fluoride deprotected, the resulting alcohol can be converted to a thiol, and then oxidized to the sulfonic acid 123. Ozonolysis with reductive workup, mesylate formation, azide displacement and hydrogenation followed by cyclization can provide sulfonamide 124. Fluoride deprotection and Swern oxidation can give aldehyde 125. Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 126.
Scheme 29 describes the synthesis of 4,5-disubstituted sulfonamides. The olefin 64 can be hydroborated, the resulting alcohol can be converted to a thiol, and then oxidized to the sulfonic acid 127. Selective fluoride deprotection, mesylate formation, azide displacement and hydrogenation followed by cyclization can provide sulfonamide 128. Fluoride deprotection and Swern oxidation can give aldehyde 129. Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 130.
Scheme 30 describes the synthesis of 4,5-disubstituted sulfonamides. The ether 70 can be selectively fluoride deprotected, the resulting alcohol can be converted to a thiol, and then oxidized to the sulfonic acid 131. Hydroboration of the olefin, mesylate formation, azide displacement and hydrogenation followed by cyclization can provide sulfonamide 132. Fluoride deprotection and Swern oxidation can give aldehyde 133. Alternately, the alcohol can be oxidized with PDC to the carboxylic acid 134.
Multisubstituted pyrrolidines and piperidines may be synthesized by the methods outlined in Scheme 31. Monoalkylation of 135 via an enolate using LDA or potassium hexamethyldisilazane, or converting 135 first to an enamine, or by using other bases, all of which can be done in THF, ether, dioxane, benzene, or an appropriate non-hydroxylic solvent at xe2x88x9278xc2x0 C. to room temperature with an alkylating agent such as methyl iodide, benzyl bromide, etc. where X can be as defined in Scheme 1, yields product 136. This product can subsequently undergo alkylation again under thermodynamic or kinetic conditions and afterwards, if need be, can undergo two more alkylations to produce tri- and tetrasubstituted analogs of 136. The thermodynamic or kinetic conditions yield regioselectively alkylated products (for a discussion on thermodynamic vs. kinetic alkylations see H. House Modern Synthetic Reactions, W. A. Benjamin, Inc. (Menlo Park, Calif.: 1972) chapter 9). 
Subsequent Wittig olefination yields compound 137. Hydrogenation (asymmetric hydrogenation can be an option here: Parshall, G. W. Homogeneous Catalysis, John Wiley and Sons, New York: 1980, pp. 43-45; Collman, J. P., Hegedus, L. S. Principles and Applications of Organotransition Metal Chemistry, University Science Books, Mill Valley, Calif., 1980, pp. 341-348) yields pyrrolidine or piperidine 138 which can be resolved into its relative and/or absolute isomers at this stage or later on in the synthesis either by crystallization, chromatographic techniques, or other methods familiar to one skilled in the art. The amine 138 an then be elaborated into the compounds of this invention by methods discussed previously (Scheme 1). The carbonyl-containing intermediate 136 in Scheme 31 can also be reduced to the methylene analog via a Wolff-Kishner reduction and modifications thereof, or by other methods familiar to one skilled in the art. This piperidine or pyrrolidine can be deprotected and elaborated to the compounds of this invention by methods discussed earlier. Thus, mono-, di-, tri-, or tetraalkylated carbonyl-containing pyrrolidines or piperidines can be synthesized, which in turn can be reduced to the corresponding xe2x80x94CH2-analogs employing the Wolff-Kishner reduction or other methods.
Another method for synthesizing gem-substituted pyrrolidines and piperidines can be shown in Scheme 32. It can be understood by one skilled in the art that some of the steps in this scheme can be rearranged. It can be also understood that gem-disubstitution can be only shown at only one position on the piperidine ring and that similar transformations may be performed on other carbon atoms as well, both for piperidine and pyrrolidine. Thus, 3-carboethoxypiperidine 139 may be BOC-protected and alkylated employing a base such as LDA, KHMDS, LHDMS, etc., in THF, ether, dioxane, etc. at xe2x88x9278xc2x0 C. to room temperature, and an alkylating agent R6X where X can be a halide (halide=Cl, Br, I), mesylate, tosylate or triflate, to yield 141. Reduction using DIBAL, for example, and if necessary followed by oxidation such as a Swern oxidation (S. L. Huang, K. Omura, D. Swern J. Org. Chem. 1976, 41, 3329-32) yields aldehyde 142. Wittig olefination (143) followed by deprotection yields 144 which may be elaborated as described previously into the compounds of this invention. Reduction of the Wittig adduct 143 yields 145 which may be deprotected to yield 146 which may be in turn elaborated as described previously into the compounds of this invention. Reaction of aldehyde 142 with an alkyllithium or Grignard reagent yields alcohol 147 which may be reduced catalytically or with Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) if R5* (R5*=R5 or a precursor thereof) can be aromatic to yield 148. If R5* can be not aromatic, then the OH may be reduced by the method of Barton (Barton, D. H. R.; Jaszberenyi, J. C. Tet. Lett. 1989, 30, 2619 and other references therein). Once tosylated, the alcohol can also be displaced with dialkyllithium cuprates (not shown) (Hanessian, S.; Thavonekham, B.; DeHoff, B.; J Org. Chem. 1989, 54, 5831). Deprotection if necessary yields 149 which may be elaborated as described previously into the compounds of this invention. 
A method for the alkylation of alkyl groups, arylalkyl groups, allylic groups, propargylic groups, etc., and a variety of other electrophiles onto the pyrrolidinyl and/or piperidinyl alpha-carbons (alpha to the ring nitrogen atom) can be represented by the work of Peter Beak, et al. as shown in Scheme 33. It can be understood by one skilled in the art that the R5 and R13 groups are either in their precursor, protected, or final form. Only one R5 group can be shown to be substituted on piperidine/pyrrolidine 150. However it can be understood by one skilled in the art that additional functionality may be present on the ring in either precursor, protected, or final form. Thus lithiation with an alkyllithium reagent such as n-BuLi or s-BuLi as shown, followed by quenching with an electrophilic species such as R5X or R13X where X can be as defined in Scheme 1 and R5 and R13 are in their precursor, protected, or final form, yields monoalkylated piperidine/pyrrolidine 151. This alkylation may occur either stereoselectively (P. Beak and W. K. Lee J. Org. Chem. 1990, 55, 2578-2580) or enantioselectively if sparteine can be included as a source of chirality (P. Beak, et al., J. Am. Chem. Soc. 1994, 116, 3231-3239). The alkylation process may be repeated up to three more times as shown in Scheme 33 to result in di-, tri-, and tetrasubstitution at the alpha-positions. 
A method for the synthesis of N-substituted heterocycles at R5 can be shown in Scheme 34. The heterocycle can be deprotonated with NaH or by other bases familiar to one skilled in the art, in a solvent such as DMF, THF, or another appropriate non-hydroxylic solvent and reacted with piperidine or pyrrolidine 155 at room temperature to the reflux temperature of the solvent. Deprotection and elaboration as described before yields compounds where R5 contains an N-substituted heterocycle. If the nitrogen atom of the heterocycle can be sufficiently nucleophilic, then an acid scavenger, such as K2CO3, KHCO3, Na2CO3, NaHCO3, amongst others, can be used in place of NaH, employing THF, DMF, or methyl ethyl ketone as solvents. In this case hydroxylic solvents may be used as well, such as methanol, ethanol, etc. from room temperature to the reflux temperature of the solvent. Compound 155 as well as its other positional isomers are available, for example, from commercially available 4-hydroxymethylpiperidine, 2-, 3-, and 4-carboethoxypiperidine, L- or D-proline ethyl ester, or from methyl l-benzyl-5-oxo-3-pyrrolidinecarboxylate by methods familiar to one skilled in the art and as discussed previously in this application. 
A method for the synthesis of C-substituted heterocycles at R5 can be shown in Scheme 35. Many heterocycles such as the ones shown in Scheme 35, but not limited thereto, can be metallated with strong bases such as LDA, n-BuLi, sec-BuLi, t-BuLi, etc. to yield the corresponding anionic species. These anions may also be generated via halogen-metal exchange employing n-BuLi, or other alkyllithium reagents. These reactions may be performed in THF, ether, dioxane, DME, benzene, etc. at xe2x88x9278xc2x0 C. to room temperature. 
For reviews of these metallations and halogen-metal exchange reactions see Organometallics in Organic Synthesis, FMC Corp., Lithium Division, 1993, pp. 17-39; Lithium Link, FMC Corp., Spring 1993, pp. 2-17; n-Butyllithium in Organic Synthesis, Lithium Corp. of America, 1982, pp. 8-16; G. Heinisch, T. Langer, P.
Lukavsky, J. Het. Chem. 1997, 34, 17-19. The anions can then be quenched with electrophile 155 or its positional isomers to yield the corresponding C-alkylated heterocyclic pyrrolidine or piperidine 157.
Another method for the synthesis of C-substituted heterocyclic-methylpyrrolidines or piperidines can be shown in Scheme 36. The protected aldehyde 158 can be reacted with the anion of the heterocycle (its generation as described previously) at xe2x88x9278xc2x0 C. to room temperature with or without CeCl3 in an inert solvent such as THF, ether, dioxane, DME, benzene, etc. to yield carbinol 159. Catalytic hydrogenation of the alcohol yields the corresponding methylene compound 157. Other reduction methods include Et3SiH/TFA (J. Org. Chem. 1969, 34, 4; J. Org. Chem. 1987, 52, 2226) amongst others familiar to one skilled in the art. It can be understood by one skilled in the art that the aldehyde group can be located in other positions instead of, for example, the 4-position of piperidine in compound 158 as depicted in Scheme 36. It can be to be understood that other heterocycles may also be used besides the ones shown in Scheme 35 and 36. 
The anions of the methyl-substituted heterocycles may also be reacted with a BOC-protected piperidone or pyrrolidone (160) to yield alcohols 161 as shown in Scheme 22 (see above reviews on metallations for references). These alcohols may be reduced using PtO2 and TFA (P. E. Peterson and C. Casey, J. Org. Chem. 1964, 29, 2325-9) to yield piperidines and pyrrolidines 162. These can subsequently be taken on to the compounds of this invention as described previously. It can be understood by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine in compound 160 as depicted in Scheme 37. It can be to be understood that other heterocycles may also be used besides the ones shown in Scheme 37.
One may also react aryl (phenyl, naphthyl, etc.) anions, generated either by halogen-metal exchange or by ortho-directed metallation (Snieckus, V. Chem. Rev. 1990, 90, 879-933) using n- or s- or t-BuLi in a non-hydroxylic solvent such as THF, ether, etc., with or without TMEDA and allow them to react with compounds 155, 158, and 160 with subsequent elaboration to yield the compounds of this invention by the methods depicted in Schemes 34-37.
Another method for the preparation of C-substituted heterocycles can be shown in Scheme 38. Protected piperidone 160 undergoes a Wittig reaction with heterocyclic phosphorous ylides to yield 163. Hydrogenation over a noble metal catalyst such as Pd in an alcoholic solvent or with an optically active transition metal catalyst (see asymmetric hydrogenation references of Parshall and Coleman, op. cit.) yields 164 which can be further elaborated into the compounds of this invention by the procedures described previously. It will be appreciated by one skilled in the art that the carbonyl group can be located in other positions instead of, for example, the 4-position of piperidine in compound 160 as depicted in Scheme 38. It can be to be understood that other heterocycles may also be used besides the ones shown in Scheme 38.
Syntheses of amines 9, 10, and the amines which are precursors to isocyanates or isothiocyanates 5 will now be discussed. For example, nitrobenzeneboronic acid (165: Scheme 39) can undergo Suzuki couplings (Suzuki, A. Pure Appl. Chem. 1991, 63, 419) with a wide variety of substituted iodo- or bromo aryls (aryls such as phenyl, naphthalene, etc.), heterocycles, alkyls, akenyls (Moreno-manas, M., et al., J. Org. Chem., 1995, 60, 2396), or alkynes. It can also undergo coupling with triflates of aryls, heterocycles, etc. (Fu, J.-m, Snieckus, V. Tet. Lett. 1990, 31, 1665-1668). Both of the above reactions can also undergo carbonyl insertion in the presence of an atmosphere of carbon monoxide (Ishiyama, et al., Tet. Lett. 1993, 34, 7595). These nitro-containing compounds (167 and 169) can then be reduced to the corresponding amines either via catalytic hydrogenation, or via a number of chemical methods such as Zn/CaCl2 (Sawicki, E. J Org Chem 1956, 21). The carbonyl insertion compounds (158) can also undergo reduction of the carbonyl group to either the CHOH or CH2 linkages by methods already discussed (NaBH4 or Et3SiH, TFA, etc.). These amines can then be converted to isocyanate 5 via the following methods (Nowakowski, J. J Prakt Chem/Chem-Ztg 1996, 338 (7), 667-671; Knoelker, H.-J.et al., Angew Chem 1995, 107 (22), 2746-2749; Nowick, J. S.et al., J Org Chem 1996, 61 (11), 3929-3934; Staab, H. A.; Benz, W.; Angew Chem 1961, 73); to isothiocyanate 5 via the following methods (Strekowski L. et al., J Heterocycl Chem 1996, 33 (6), 1685-1688; Kutschy, Pet al., Synlett 1997, (3), 289-290); to carbamoyl chloride 11 (after 1168 or 170 can be reductively aminated with an R2 group) (Hintze, F.; Hoppe, D.; Synthesis (1992) 12, 1216-1218); to thiocarbamoyl chloride 11 (after 168 or 170 can be reductively aminated with an R2 group) (Ried, W.; Hillenbrand, H.; Oertel, G.; Justus Liebigs Ann Chem 1954, 590); or just used as 9, or 10 (after 168 or 170 can be reductively aminated with an R2 group), in synthesizing the compounds of this invention by the methods depicted in Scheme 1.
Likewise, protected aminobromobenzenes or triflates or protected aminobromoheterocycles or triflates 171 (Scheme 40) may undergo Suzuki-type couplings with arylboronic acids or heterocyclic boronic acids (172). These same bromides or triflates 171 may also undergo Stille-type coupling (Echavarren, A. M., Stille, J. K. J. Am. Chem. Soc., 1987, 109, 5478-5486) with aryl, vinyl, or heterocyclic stannanes 175. Bromides or triflates 171 may also undergo Negishi-type coupling with other aryl or heterocyclic bromides 176 (Negishi E. Accts. Chem. Res. 1982, 15, 340; M. Sletzinger, et al., Tet. Lett. 1985, 26, 2951). Deprotection of the amino group yields an amine with can be coupled to make a urea and other linkers containing Z as described above and for Scheme 1. Amino protecting groups include phthalimide, 2,4-dimethyl pyrrole (S. P. Breukelman, et al. J. Chem. Soc. Perkin Trans. I, 1984, 2801); N-1,1,4,4-Tetramethyldisilyl-azacyclopentane (STABASE) (S. Djuric, J. Venit, and P. Magnus Tet. Lett 1981, 22, 1787) and others familiar to one skilled in the art. 
Many amines are commercially available and can be used as 9, 10, or used as precursors to isocyanates or isothiocyanates 5. There are numerous methods for the synthesis of non-commercially available amines familiar to one skilled in the art. For example, aldehydes and ketones may be converted to their O-benzyl oximes and then reduced with LAH to form an amine (Yamazaki, S.; Ukaji, Y.; Navasaka, K.; Bull Chem Soc Jpn 1986, 59, 525). Ketones and trifluoromethylketones undergo reductive amination in the presence of TiCl4 followed by NaCNBH4 to yield amines (Barney, C. L., Huber, E. W., McCarthy, J. R. Tet. Lett. 1990, 31, 5547-5550).
Aldehydes and ketones undergo reductive amination with Na(AcO)3BH as mentioned previously to yield amines (Abdel-Magid, A. F., et al. Tet. Lett. 1990, 31, (39) 5595-5598). Amines may also be synthesized from aromatic and heterocyclic OH groups (for example, phenols) via the Smiles rearrangement (Weidner, J. J., Peet, N. P. J. Het. Chem., 1997, 34, 1857-1860). Azide and nitrile displacements of halides, tosylates, mesylates, triflates, etc. followed by LAH or other types or reduction methods yield amines. Sodium diformyl amide (Yinglin, H., Hongwen, H. Synthesis 1989 122), potassium phthalimide, and bis-BOC-amine anion can all displace halides, tosylates, mesylates, etc., followed by standard deprotection methods to yield amines, procedures which are familiar to one skilled in the art. Other methods to synthesize more elaborate amines involve the Pictet-Spengler reaction, imine/immonium ion Diels-Alder reaction (Larsen, S. D.; Grieco, P. A. J. Am. Chem. Soc. 1985, 107, 1768-69; Grieco, P. A., et al., J. Org. Chem. 1988, 53, 3658-3662; Cabral, J. Laszlo, P. Tet. Lett. 1989, 30, 7237-7238; amide reduction (with LAH or diborane, for example), organometallic addition to imines (Bocoum, A. et al., J. Chem. Soc. Chem. Comm. 1993, 1542-4) and others all of which are familiar to one skilled in the art.
Compounds where Zxe2x95x90Nxe2x80x94CN, CHNO2, and C(CN)2 can be synthesized by the methods shown in Scheme 41. Thus amine 108 reacts with malononitrile 179 neat or in an inert solvent at room temperature to the reflux temperature of the solvent, or at the melting point of the solid/solid mixture, to yield malononitrile 178. This in turn can undergo reaction with amine 177 under similar conditions stated just above to yield molononitrile 181. Likewise, a similar reaction sequence may be used to make 184 and 187 [for Zxe2x95x90C(CN)2], see for example P. Traxler, et al., J. Med. Chem. (1997), 40, 3601-3616; for Zxe2x95x90Nxe2x80x94CN, see K. S. Atwal, J. Med. Chem. (1998) 41, 271; for Zxe2x95x90CHNO2, see J. M. Hoffman, et al., J. Med. Chem. (1983) 26, 140-144). 
Additionally, the starting materials in the Schemes 6 through 29 can be modified with an a one-carbon longer or shorter length chain or ring size starting material and be applicable to the synthesis of five and seven-membered ring analogs. In some of the synthetic schemes, an intermediate may be easily modified to lengthen or shorten the chain length as shown in Scheme 42. To homologate alcohol 188, the mesylate can be displaced with cyanide. Lithium aluminum hydride reduction of the nitrile can give the amine 189. Alternatively, basic hydrolysis of the nitrile and lithium aluminum hydride reduction of the resulting acid can give the alcohol 190. To decrease the chain by one carbon, the mesylate of alcohol 188 can be eliminated to the olefin which upon treatment with ozone and reductive workup can give alcohol 191. In those schemes where an olefin can be hydroborated, to reduce the chain size by one carbon, the hydroboration step may be replaced with ozonolysis with an reductive workup (not shown in Scheme 42). 
Scheme 43 describes the synthesis of carbamate- and urea-containing heterocycles. Olefin 70 can undergo ozonolysis with reductive workup, mesylate formation, azide displacement and catalytic reduction to give amine 192. Selective fluoride deprotection followed by ring closure with carbonyl diimidazole (Kaiser, A.; Balbi, M.; Tetrahedron: Asymmetry 1999, 10(5), 1001) can give carbamate 193. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 194. Alternatively, oxidation with PDC can give acid 195. While only one regioisomer and ring size is shown, other regioisomers and ring sizes can be prepared by varying the chain lengths relative to the chiral centers as shown in the preceding schemes and then performing the ring closure. 
Scheme 44 describes the preparation of cyclic ureas, olefin 70 can undergo ozonolysis with reductive workup, mesylate formation, azide displacement and selective fluoride deprotection to give azide 196. Mesylate formation, azide displacement, catalytic hydrogenation followed by ring closure with carbonyl diimidazole can give urea 197. Fluoride deprotection and Swern oxidation completes the synthesis of aldehyde 198. Alternatively, oxidation with PDC can give acid 199.
The regioisomeric 3,4-disubstituted dihydropyrans prepared in Scheme 11 can also be prepared using the route shown in Scheme 45. Acid-catalyzed trans-esterification of xcex3-butyrolactone 200 can provide the hydroxyester 201, which can undergo rhodium-catalyzed carbene insertion to provide the diester 202. Dieckmann cyclization can provide the ketoester 203, which can be converted to the xcex2-aminoester 205 as already described for the preparation of other xcex2-aminoesters. The trans isomer can be obtained either by reduction of the intermediate enamine 204 with sodium triacetoxyborohydride followed by base-catalyzed epimerization as already described, or by reduction of 204 with triethylsilane in trifluoroacetic acid. The ester can then be hydrolyzed to the acid 206, followed by coupling to give the amide 207. The benzyl group can be removed by hydrogenolysis to the amine 208, followed by reduction of the amide to 209 and reaction with an isocyanate or carbamate to provide the products 210.
A number of 5-membered heterocyclic xcex2-ketoesters can be prepared using methods demonstrated in the literature, and converted to the analogous products using reaction sequences similar to those already described. For example as in Scheme 46, methyl 4-keto-tetrahydrothiophene-3-carboxylate 211 and methyl 3-keto-tetrahydrothiophene-2-carboxylate 212 can be prepared as described by O. Hromatka, D. Binder and K. Eichinger, Monatsheft. Chem. 1973, 104, 1520. Ethyl 4-ketopyrrolidine-3-carboxylate 213 and ethyl 3-ketopyrrolidine-2-carboxylate 214, bearing a carbamate protecting group on the ring nitrogen atom, may be prepared as described by J. Blake, C. D. Willson and H. Rapoport, J. Am. Chem. Soc. 1964, 86, 5293, and converted to various products using chemistry analogous to that already described.
A synthetic route to (3R, 4S)-4-[(R)-1-phenylethylamino]-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester 215 has been described by X. Wang, J. F. Espinosa and S. H. Gellman, J. Am. Chem. Soc. 2000, 122, 4821. A synthetic route to (2R, 3R)-3-benzyloxycarbonylamino-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-ethyl ester 216 has been described by S. H. Gellman, D. H. Appella, L. A. Christianson, D. A. Klein, S. Krauthauser, Y. J. Chung, and X. Wang, U.S. Pat. No. 6,060,585. The preparation of 1-substituted analogs of (3R,4S)-4-tert-butoxycarbonylamino-5-oxo-pyrrolidine-3-carboxylic acid benzyl ester 217 has been described by D. S. Garvey, P. D. May and A. M. Nadzan, J. Org. Chem. 1990, 55, 936. The preparation of the enantiomer of N-benzyl-N-[(2R,3R)-2-formyl-5-oxo-pyrrolidin-3-yl]-acetamide 218 has been described by N. Langlois and M. Radom, Tetrahedron Lett 1998, 39, 857. These intermediates may be converted to the corresponding final products using synthetic transformations disclosed herein.